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WO2021142132A1 - Compositions et procédés pour le traitement d'une maladie par manipulation du métabolisme de la sérine - Google Patents

Compositions et procédés pour le traitement d'une maladie par manipulation du métabolisme de la sérine Download PDF

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WO2021142132A1
WO2021142132A1 PCT/US2021/012516 US2021012516W WO2021142132A1 WO 2021142132 A1 WO2021142132 A1 WO 2021142132A1 US 2021012516 W US2021012516 W US 2021012516W WO 2021142132 A1 WO2021142132 A1 WO 2021142132A1
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substituted
unsubstituted
inhibitor
serine
certain embodiments
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Joshua D. Rabinowitz
Lifeng Yang
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Princeton University
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Princeton University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • NADH provides high energy electrons to the electron transport chain (ETC) for ATP production.
  • ETC electron transport chain
  • NADH accumulation can be toxic.
  • mammalian cells typically downregulate TCA metabolism and associated NADH production.
  • NADH levels remain at undesirably high levels.
  • the present disclosure generally relates to compositions and methods for manipulating serine catabolism for treating NADH-related disorders, such as, e.g., respiration impairment.
  • the disclosure provides methods of treating disorders associated with excess NADH, such as, e.g., respiration impairment, in a subject (e.g., a subject in need thereof), comprising administering an effective amount of an inhibitor of serine metabolism to the subject.
  • the disclosure provides methods of treating disorders associated with excess NADH, such as, e.g., respiration impairment, in a subject (e.g., a subject in need thereof), comprising administering an effective amount of an inhibitor of serine catabolism to the subject.
  • the disorder is caused by hypoxia.
  • the disorder is caused by an ischemia.
  • the disorder is caused by a tumor.
  • the disorder is caused by impaired oxygenation due to excess adipose tissue.
  • the disorder is caused by an ischemic event.
  • the respiration impairment is caused by a genetic deficiency of the electron transport chain. In other embodiments, the respiration impairment is caused by Leigh syndrome.
  • the inhibitor of serine catabolism is an antifolate.
  • the inhibitor comprises a compound that inhibits (e.g., blocks)
  • the inhibitor is KDG112.
  • the subject has received an electron transport chain inhibitor.
  • the disclosure provides methods of treating a disorder associated with excess NADH, such as, e.g., respiration impairment, in a subject (e.g., a subject in need thereof), comprising modulating serine metabolism in the subject.
  • the disclosure provides methods of treating a disorder associated with excess NADH, such as, e.g., respiration impairment, in a subject (e.g., a subject in need thereof), comprising modulating serine catabolism in the subject.
  • a disorder associated with excess NADH such as, e.g., respiration impairment
  • the respiration impairment is caused by a genetic deficiency of the electron transport chain. In further embodiments, the respiration impairment is caused by Leigh syndrome.
  • the modulating comprises inhibiting serine catabolism.
  • the disorder is caused by hypoxia (e.g., anoxia). In some embodiments, the disorder is caused by an ischemia. In some embodiments, the disorder is caused by a tumor. In some embodiments, the disorder is caused by impaired oxygenation due to excess adipose tissue. In some embodiments, the disorder is caused by an ischemic event.
  • the disclosure provides methods of treating a mitochondrial disorder in a subject (e.g., a subject in need thereof), comprising administering a composition that modulates the mitochondrial serine catabolic pathway.
  • the composition comprises a compound that inhibits SHMT2, MTHFD2 or a combination thereof.
  • the composition comprises KDG112.
  • the disclosure provides a method of treating a mitochondrial disorder in a subject (e.g., a subject in need thereof), comprising administering an effective amount of an inhibitor of serine metabolism (e.g., an inhibitor of serine catabolism) to the subject, wherein the inhibitor of serine metabolism inhibits mitochondrial serine metabolism (e.g., mitochondrial serine catabolism).
  • an inhibitor of serine metabolism e.g., an inhibitor of serine catabolism
  • mitochondrial serine metabolism e.g., mitochondrial serine catabolism
  • the inhibitor of serine metabolism is an inhibitor of SHMT2 and/or MTHFD2.
  • the disclosure provides methods for treating a disease involving deficient respiration in a subject (e.g., a subject in need thereof), comprising administering a therapeutically effective amount of an inhibitor of serine metabolism to the subject.
  • the disease is a genetically inherited mitochondrial disorder. In some embodiments, the disease is myocardial infarction or stroke.
  • the inhibitor of serine metabolism is an antifolate.
  • the inhibitor inhibits SHMT2, MTHFD2 or a combination thereof.
  • the disclosure provides methods for treating a mitochondrial disease in a subject (e.g., a subject in need thereof), comprising administering a diet or dietary supplement deficient in serine compared to other amino acids to the subject.
  • the disclosure provides a method of improving the therapeutic index of an electron transport chain inhibitor (e.g., metformin, IACS-10759) in a subject (e.g., a subject in need thereof), comprising administering to the subject a therapeutically effective amount of an inhibitor of serine metabolism (e.g., an inhibitor of serine catabolism), wherein the subject is receiving the electron transport chain inhibitor in combination with the inhibitor of serine metabolism.
  • an electron transport chain inhibitor e.g., metformin, IACS-10759
  • an inhibitor of serine metabolism e.g., an inhibitor of serine catabolism
  • the disclosure provides methods of improving the therapeutic index of metformin in a subject (e.g., a subject in need thereof), comprising administering a therapeutically effective amount of an inhibitor of serine metabolism to the subject.
  • the disclosure provides a method for improving the effectiveness of an electron transport chain inhibitor (e.g., metformin, IACS-10759) in a subject (e.g., a subject in need thereof), comprising administering to the subject an effective amount of a serine supplement, wherein the subject is receiving the electron transport chain inhibitor in combination with the serine supplement.
  • an electron transport chain inhibitor e.g., metformin, IACS-10759
  • the disclosure provides methods for improving the effectiveness of metformin in a subject (e.g., a subject in need thereof), comprising administering a serine supplement to the subject.
  • the disclosure provides methods of treating a tumor in a subject (e.g., a subject in need thereof), comprising administering to the subject an effective amount of an activator of serine catabolism.
  • the method further comprises administering an electron transport chain inhibitor to the subject.
  • the electron transport chain inhibitor can be metformin, phenformin, rotenone, deguelin, antimycin, oligomycin, or a combination thereof.
  • FIGs. 1 A-1G show that serine catabolism feeds NADH in vivo.
  • FIG. 1 A Schematic showing folate-mediated serine catabolism and its tracing with [2,3,3- 2 H]serine. This tracer has traditionally been used to distinguish cytosolic versus mitochondrial production of 1C units from serine, with the cytosolic pathway yielding M+2 thymidine and the mitochondrial pathway yielding MTl thymidine. Smaller filled circles indicate labeled hydrogens (deuteriums). The cytosolic pathway (blue) yields M+2 thymidine and the mitochondrial pathway (red) yields M+l thymidine.
  • FIG. 1 A Schematic showing folate-mediated serine catabolism and its tracing with [2,3,3- 2 H]serine. This tracer has traditionally been used to distinguish cytosolic versus mitochondrial production of 1C units from serine, with the cytosolic pathway yielding M+2 thymidine and the
  • FIG. 1C Raw orbitrap mass spectrum of M+l malate in pancreas after [2,3,3- 2 H]serine infusion, showing the 2 H peak well-resolved from the natural abundance 13 C peak.
  • FIG. IE Raw mass spectrum of M+l pyruvate in pancreas after [2,3,3- 2 H]serine infusion. Lack of pyruvate labeling rules out serine labeling malate via the pyruvate pathway.
  • FIG. IF [2,3,3-2H]serine labels NADH more than malate. Data are fractional 2H-labeling of malate relative to tissue serine labeling (mean ⁇ SD, N>4).
  • FIG. 1G Raw FTICR mass spectrum of M+l NADH in pancreas and heart after [2,3,3-2H]serine infusion.
  • FIGs. 2A-2F show that serine catabolism is a major NADH source when respiration is impaired.
  • FIG. 2A Schematic of mitochondrial NADH sources.
  • FIG. 2B Fractional 2 H-labeling of NADH from the indicated 2 H-labeled glutamine (gin), lactate (lac), palmitate (pal), or serine (ser).
  • FIG. 2C Oxygen consumption rate and fraction NAD 2 H from [2,3,3- 2 H] serine as a function of metformin concentration (mean ⁇ SD, N>4).
  • FIGs. 3A-3E show that NADH/NAD+ ratio dictates serine’s NADH contribution.
  • FIG. 3A Schematic of electron transport chain.
  • FIG. 3B Fraction NAD 2 H from [2,3,3- 2 H]serine in the presence of the ImM rotenone, 500 nM atpenin, ImM antimycin, or ImM M oligomycin or electron transport chain deficient cells (pO) (mean ⁇ SD, N>3).
  • FIG. 3C Correlation of fraction NAD 2 H from [2,3,3- 2 H] serine with intracellular NADH/NAD ratio (relative to DMEM without metformin).
  • FIG. 3D Duroquinone (DQ) and pyruvate can serve as electron acceptors to convert NADH into NAD.
  • DQ Duroquinone
  • pyruvate can serve as electron acceptors to convert NADH into NAD.
  • FIGs. 4A-4F show that high NADH/NAD+ shuts off other NADH sources but not serine catabolism.
  • FIG. 4A Decrease in [U- 13 C]glucose entry into TCA cycle with increasing cellular NADH/NAD+.
  • FIG. 4B Decrease in [U- 13 C]glutamine oxidation (glutamine is instead metabolized reductively, see Supplementary Fig. 11D).
  • FIG. 4C Initial increase, followed by decrease, in [U- 13 C]palmitate entry into TCA cycle.
  • FIG. 4D Maintenance of mitochondrial serine catabolism indicated by M+l dTTP from [2,3,3- 2 H]serine (see Fig. 1 A).
  • FIG. 4E Quantification of intracellular NAD(H) concentration with metformin treatment (the increase in NADH/NAD ratio with metformin treatment is largely driven by NADH accumulation).
  • PDH pyruvate dehydrogenase
  • KGDH a-ketoglutarate dehydrogenase
  • MDH malate dehydrogenase
  • MTHFD2 MTHFD2 enzyme activity with increasing NADH as the competitive inhibitor
  • FIGs. 5 A-5F show that loss of mitochondrial serine catabolism paradoxically facilitates cell growth in respiration-impaired cells.
  • FIG. 5A NADH/NAD for wild type and MTHFD2 knockout HCT116 cells ⁇ metformin (mean ⁇ SD, N>6).
  • FIG. 5B Schematic of links between NADH/NAD, aspartate, and nucleotide synthesis.
  • FIGs. 5C-E Intracellular aspartate (FIG. 5C), IMP/ AMP ratio (FIG. 5D) and cell number (FIG. 5E) for wild type and MTHFD2 deficient HCT116 in the presence and absence of the indicated concentration of metformin (mean ⁇ SD, N>6).
  • FIG. 5C Intracellular aspartate
  • IMP/ AMP ratio FIG. 5D
  • FIG. 5E cell number
  • FIGs. 6A-6I show that hypoxia induces serine-dependent NADH production.
  • FIG. 6A NADH/NAD+ in normoxia and hypoxia (mean ⁇ SD, N>8).
  • FIG. 6B Fraction NAD 2 H from 2 H-labeled nutrients in wild-type HCT116 cells in normoxia and hypoxia (tracers as in Fig. 2 A, mean ⁇ SD, N>3).
  • FIGs. 7A-7F show that serine catabolism provides NADH in fibroblasts derived from Leigh Syndrome patients and NDUFS4-/- mice.
  • FIG. 7D Increased malate labeling from [2,3,3-2H]serine in NDUFS4-/- mice in vivo.
  • FIGs. 8A-8F Serine catabolism feeds NADH in vivo.
  • FIG. 8A Raw mass spectrum of MTl malate, MTl 2 H pyruvate and M+2 2 H pyruvate in KPC pancreatic tumor after [2,3,3- 2 H] serine infusion.
  • FIG. 8B Raw FTICR mass spectrum of M+l NAD in pancreas and heart after [2,3,3-2H]serine infusion.
  • FIG. 8C Schematic of the conversion of U- 13 C serine into TCA cycle metabolites by serine dehydratase (SDS).
  • FIG. 8D [2,3,3-2H]serine labels malate more than aspartate.
  • FIG. 8E Relative expression level of MTHFD2 across different tissues.
  • FIGs. 9A-9D Serine catabolism is a major NADH source when respiration is impaired.
  • FIG. 9A Schematic showing glutaminolysis and its tracing with [2,3,3,4,4- 2 H] glutamine. This tracer will generate NAD2H following the enzymatic activities of glutamate dehydrogenase and malate dehydrogenase.
  • FIG. 9B Schematic showing lactate into TCA cycle and its tracing with [3,3,3- 2 H] lactate.
  • FIG. 9C Oxygen consumption rate and fraction NAD 2 H from [2,3,3-2H] serine as a function of phenformin concentration (mean ⁇ SD, N>3).
  • FIGs. 10A-10F NADH/NAD+ ratio dictates serine’s NADH contribution.
  • FIG. 10A Relative NADH/NAD+ in the presence of the ImM rotenone, 500 nM atpenin, ImM antimycin, or ImM oligomycin or electron transport chain deficient cells (pO) (mean ⁇ SD, N>3).
  • C NADH/NAD ratio and fraction NAD 2 H from [2,3,3- 2 H]serine as a function of metformin treatment duration (mean ⁇ SD, N>3).
  • Mitochondrial pyruvate carrier inhibitor (UK5099) does not block pyruvate rescue of NADH phenotypes (mean ⁇ SD, N>5). ** p ⁇ 0.01, *** p ⁇ 0.001 by two-tailed student's /-test.
  • FIGs. 11 A-l 1 J High NADH/NAD+ shuts off other NADH sources but not serine catabolism.
  • FIGs. 11 A-l 1C Schematic showing U- 13 C glucose (A), U- 13 C glutamine (B), U- 13 C palmitate (C) are catabolized into TCA cycle metabolites as well as generating NADH at the function of different dehydrogenases.
  • FIG. 11D Increase in [U- 13 C]glutamine reductive carboxylation.
  • FIG. 1 IE Initial increase, followed by decrease, in [U- 13 C]palmitate entry into TCA cycle, indicated from M+2 a-ketoglutarate.
  • FIG. 11G Decrease in [U- 13 C]glucose entry into TCA cycle with increasing cellular NADH/NAD.
  • FIG. 11H Decrease in [U- 13 C] glutamine oxidation.
  • FIG. I ll Malate labeling from [U- 13 C]palmitate confirms that the fractional contribution of fatty acid oxidation to TCA initially increases, and then decreases, as NADH/NAD rises.
  • FIG. 11 J De novo serine synthesis from [U- 13 C]glucose.
  • FIG. 12 Higher NADH inhibitory constant for MTHFD2 compared to MDH.
  • FIGs. 13A-13H Loss of mitochondrial serine catabolism paradoxically facilitates cell growth in respiration-impaired cells.
  • FIG. 13B Aspartate isotopic forms abundance in HCT116 cells fed [U- 13 C]glutamine plus the indicated respiratory chain inhibitors (mean ⁇ SD, N>3).
  • FIGs. 14A-14F Impact of genetic respiratory chain deficiency on glucose, glutamine and serine metabolism.
  • FIG. 14C MTOl deficient HCT116 growth rate in normal DMEM medium ⁇ the indicated concentration of the serine catabolism inhibitor SHINl (mean ⁇ SD, N>4).
  • FIGs. 15A-15E Serine catabolism provides NADH in NDUFS4 deficient T cells and C2C12 cells treated with metformin.
  • FIGs. 16A-16C (**p ⁇ 0.01, ***p ⁇ 0.001 by two-tailed Student’s t test).
  • FIG. 16B IACS-10759 increased NADH/NAD of HCT116 xenograft tumors.
  • any formula depicted herein is intended to represent a compound of that structural formula as well as certain variations or forms.
  • a formula given herein is intended to include a racemic form, or one or more enantiomeric, diastereomeric, or geometric isomers, or tautomeric forms, or a mixture thereof.
  • any formula given herein is intended to refer also to a solvate, such as a hydrate, solvate, or polymorph of such a compound, or a mixture thereof.
  • any formula given herein is intended to refer to amorphous and/or crystalline physical forms of the compound.
  • the compounds described herein may be analytically pure, or a mixture in which the compound comprises at least 50%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 98% by weight of the mixture.
  • alkoxy refers to an oxygen atom having an alkyl group attached thereto.
  • Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.
  • a straight chain or branched chain alkoxy has 30 or fewer carbon atoms, and preferably 20 or fewer, such as Ci-Ci 0 alkoxy, Ci-C 8 alkoxy, or Ci-C 6 alkoxy.
  • alkenyl refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyls" and “substituted alkenyls", the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive.
  • alkenyl groups substitution of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.
  • a straight chain or branched chain alkenyl has 30 or fewer carbon atoms, and preferably 20 or fewer, such as C 2 -Ci 0 alkenyl or C 2 - C 8 alkenyl.
  • alkynyl refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyls" and “substituted alkynyls,” the latter of which refers to alkynyl moieties having substituents replacing one or more hydrogens on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive.
  • a straight chain or branched chain alkynyl has 30 or fewer carbon atoms, and preferably 20 or fewer, such as C 2 -Ci 0 alkynyl or C 2 - C 8 alkynyl.
  • alkyl refers to a saturated aliphatic groups, including straight-chain alkyl groups, and branched-chain alkyl groups.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g ., Ci-C 30 for straight chains, C 3 -C 30 for branched chains), and more preferably 20 or fewer.
  • alkyl groups are lower alkyl groups, e.g., methyl, ethyl, «-propyl, /-propyl, «-butyl and «-pentyl.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g ., Ci-C 30 for straight chains, C3-C30 for branched chains).
  • the chain has ten or fewer carbon (C1-C10) atoms in its backbone.
  • the chain has eight or fewer carbon (Ci-C 8 ) atoms.
  • the chain has six or fewer carbon (Ci-C 6 ) atoms in its backbone.
  • a Ci-C 6 straight chained or branched alkyl group is also referred to as a "lower alkyl" group.
  • alkyl (or “lower alkyl”) as used throughout the disclosure, examples, and claims is intended to include both “unsubstituted alkyls” and “substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • Such substituents can include, but not limited to, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, an alkylthio, an acyloxy, a phosphoryl, a phosphate, a phosphonate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aryl
  • the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.
  • the substituents of a substituted alkyl may include substituted and unsubstituted forms of hydroxyl, halo, amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF 3 , -CN and the like.
  • Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF 3 , -CN, and the like.
  • arylkyl refers to an alkyl group substituted with one or more aryl groups.
  • aryl includes substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon.
  • the ring is a 5- to 7- membered ring, more preferably a 6-membered ring.
  • Aryl groups include phenyl, phenol, aniline, and the like.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g ., a moiety that can be represented by ⁇ w erein each R 30 independently represents a hydrogen or a hydrocarbyl group, or two R 30 are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • aminoalkyl refers to an alkyl group substituted with an amino group.
  • amide refers to a group: n c R , wherein each R 30 independently represent a hydrogen or hydrocarbyl group, or two R 30 are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • nitrile or "cyano,” as used herein, refers to -CN.
  • carbocycle refers to a saturated or unsaturated ring in which each atom of the ring is carbon.
  • carbocycle includes both aromatic carbocycles and non-aromatic carbocycles.
  • Non-aromatic carbocycles include both cycloalkane rings, in which all carbon atoms are saturated, and cycloalkene rings, which contain at least one double bond.
  • Carbocycle includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings.
  • Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings.
  • the term “fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring.
  • Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings.
  • an aromatic ring e.g. , phenyl
  • Exemplary “carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3- ene, naphthalene and adamantane.
  • Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-lH-indene and bicyclo[4.1.0]hept-3-ene.
  • “Carbocycles” may be substituted at any one or more positions capable of bearing a hydrogen atom.
  • cycloalkyl refers to the radical of a saturated aliphatic ring.
  • cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably from 5-7 carbon atoms in the ring structure.
  • Suitable cycloalkyls include cycloheptyl, cyclohexyl, cyclopentyl, cyclobutyl and cyclopropyl.
  • Cycloalkyl includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings.
  • fused cycloalkyl refers to a bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring.
  • the second ring of a fused bicyclic cycloalkyl may be selected from saturated, unsaturated, and aromatic rings.
  • a “cycloalkenyl” group refers to a cyclic hydrocarbon containing one or more double bonds.
  • a “cycloalkynyl” group is a cyclic hydrocarbon containing one or more triple bonds.
  • polycyclyl refers to two or more rings (e.g ., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g. , the rings are “fused rings”.
  • Each of the rings of the polycycle can be substituted or unsubstituted.
  • each ring of the poly cycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.
  • halo and “halogen”, as used herein, means halogen and includes chloro, fluoro, bromo, and iodo.
  • haloalkyl means an alkyl group substituted with one or more halogens. When more than one halogen is present, the halogens may be the same or different.
  • haloalkyl groups include, but are not limited to, fluorom ethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, and the like.
  • haloalkoxy means an alkoxy group substituted with one or more halogens. When more than one halogen is present, the halogens may be the same or different.
  • haloalkyl groups include, but are not limited to, difluorom ethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, and the like.
  • heteroarylakyl refers to an alkyl group substituted with a heteroaryl group.
  • heteroaryl includes substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom (e.g ., O, N, or S), preferably one to four, or one to 3 heteroatoms, more preferably one or two heteroatoms. When two or more heteroatoms are present in a heteroaryl ring, they may be the same or different.
  • heteroatom e.g ., O, N, or S
  • heteroaryl groups include, but are not limited to, pyrrole, furan, thiophene, imidazole, tetrazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like.
  • heteroaryl also include substituted or unsubstituted “polycyclic” ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • heteroatom means an atom of any element other than carbon or hydrogen.
  • exemplary heteroatoms include but are not limited to nitrogen, oxygen, and sulfur.
  • heterocyclyl refers to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • the ring structure is saturated, such as heterocycloalkyls; in other embodiments, the ring structure is unsaturated, such as heterocycloalkenyls or heterocycloalkynyls.
  • heterocyclyl and “heterocyclic” also include substituted or unsubstituted polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.
  • the ring structure can have two cyclic rings.
  • the two cyclic rings can have two or more atoms in common, e.g, the rings are “fused rings.”
  • Heterocyclyl groups include, but no limitted to, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g ., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, an alkylthio, an acyloxy, a phosphoryl, a phosphate, a phosphonate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or
  • references to chemical moieties herein are understood to include substituted variants.
  • reference to an “alkyl” group or moiety implicitly includes both substituted and unsubstituted variants.
  • the term “unsubstituted” refers to that the specified group bears no substituents.
  • ring or “ring system”, unless context indicates otherwise, may include monocyclic rings or polycyclic rings, such as bicyclic rings.
  • ring refers to a polycyclic or bicyclic ring, each ring is independently selected from saturated or unsaturated, and either or both rings may contain one or more heteroatoms, preferably a total of 0, 1, 2, 3 or 4 heteroatoms across the ring system.
  • Compounds described herein can exist as various “solvates” or “hydrates.”
  • a “hydrate” is a compound that exists in a composition with water molecules.
  • the composition can include water in stoichiometic quantities, such as a monohydrate or a dihydrate, or can include water in random amounts.
  • a “solvate” is a similar composition except that a solvent other that water, such as with methanol, ethanol, dimethylformamide, diethyl ether and the like replaces the water.
  • a solvent other that water such as with methanol, ethanol, dimethylformamide, diethyl ether and the like replaces the water.
  • methanol or ethanol can form an “alcohol ate,”” which can again be stoichiometic or non-stoichiometric.
  • Mixtures of such solvates or hydrates can also be prepared.
  • the source of such solvate or hydrate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.
  • the compounds described herein, including their pharmaceutically acceptable salts, can exist as various polymorphs, pseudo-polymorphs, or in amorphous state.
  • polymorph refers to different crystalline forms of the same compound and other solid state molecular forms including pseudo-polymorphs, such as hydrates, solvates, or salts of the same compound.
  • pseudo-polymorphs such as hydrates, solvates, or salts of the same compound.
  • Different crystalline polymorphs have different crystal structures due to a different packing of molecules in the lattice, as a result of changes in temperature, pressure, or variations in the crystallization process. Polymorphs differ from each other in their physical properties, such as x-ray diffraction characteristics, stability, melting points, solubility, or rates of dissolution in certain solvents.
  • crystalline polymorphic forms are important aspects in the development of suitable dosage forms in pharmaceutical industry.
  • a “pharmaceutically acceptable” substance is suitable for use in contact with cells, tissues or organs of animals or humans without excessive toxicity, irritation, allergic response, immunogenicity or other adverse reactions, in the amount used in the dosage form according to the dosing schedule, and commensurate with a reasonable benefit/risk ratio.
  • a “pharmaceutically acceptable” substance that is a component of a pharmaceutical composition is, in addition, compatible with the other ingredient(s) of the composition.
  • pharmaceutically acceptable excipient encompass, without limitation, pharmaceutically acceptable inactive ingredients, materials, compositions and vehicles, such as liquid fillers, solid fillers, diluents, excipients, carriers, solvents and encapsulating materials.
  • Carriers, diluents and excipients also include all pharmaceutically acceptable dispersion media, coatings, buffers, isotonic agents, stabilizers, absorption delaying agents, antimicrobial agents, antibacterial agents, antifungal agents, adjuvants, and so on.
  • the present disclosure encompasses the use of conventional excipients, carriers and diluents in pharmaceutical compositions. See, e.g., Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (Philadelphia, Pennsylvania, 2005); Handbook of Pharmaceutical Excipients, 5th Ed., Rowe et ah, Eds., The Pharmaceutical Press and the American Pharmaceutical Association (2005); Handbook of Pharmaceutical Additives, 3rd Ed., Ash and Ash, Eds., Gower Publishing Co. (2007); and Pharmaceutical Preformulation and Formulation, Gibson, Ed., CRC Press LLC (Boca Raton, Florida, 2004).
  • a “pharmaceutically acceptable salt” is a salt of a compound that is suitable for pharmaceutical use, including but not limited to metal salts (e.g., sodium, potassium, magnesium, calcium, etc.), acid addition salts (e.g., mineral acids, carboxylic acids, etc.), and base addition salts (e.g., ammonia, organic amines, etc.).
  • metal salts e.g., sodium, potassium, magnesium, calcium, etc.
  • acid addition salts e.g., mineral acids, carboxylic acids, etc.
  • base addition salts e.g., ammonia, organic amines, etc.
  • “Pharmaceutically acceptable salt” is used herein to refer to a compound according to the disclosure that is a therapeutically active, non-toxic base or acid salt form of the free base form of the compound.
  • the acid addition salt form of a compound that occurs in its free form as a base can be obtained by treating said free base form with an appropriate acid such as an inorganic acid, for example, a hydrohalic such as hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and the like; or an organic acid, such as, for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclic, salicylic, p- aminosalicylic, pamoic and the like.
  • Compounds containing acidic protons may be converted into their therapeutically active, non-toxic base addition salt form, e.g., metal or amine salt, by treatment with appropriate organic and inorganic bases.
  • Appropriate base salt forms include, for example, ammonium salts, alkali and earth alkaline metal salts, e. g., lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e. g. N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
  • said salt forms can be converted into the free forms by treatment with an appropriate base or acid.
  • Compounds and their salts can be in the form of a solvate, which is included within the scope of the present disclosure. Such solvates include for example hydrates, alcoholates and the like. See, e.g., WO 01/062726.
  • salts include, but are not limited to, camsylate, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen- phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-l,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,
  • the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure.
  • composition refers to a composition suitable for pharmaceutical use in a subject animal, including humans and mammals, e.g., combined with one or more pharmaceutically acceptable carriers, excipients or solvents. Such a composition may also contain diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art.
  • a pharmaceutical composition encompasses a composition comprising the active ingredient(s), and the inert ingredient(s) that make up the excipient, carrier or diluent, as well as any product that results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • the pharmaceutical compositions of the present disclosure encompass any composition made by admixing a compound described herein and one or more pharmaceutically acceptable excipient(s), carrier(s) and/or diluent(s).
  • compositions comprising one or more compounds described herein and a pharmaceutically acceptable excipient(s), carrier(s) and/or diluent(s).
  • Compounds or pharmaceutical compositions of the disclosure may be used in vitro or in vivo.
  • a compound described herein or a salt (e.g., pharmaceutically acceptable salt) thereof may exhibit the phenomenon of tautomerism whereby two chemical compounds that are capable of facile interconversion by exchanging a hydrogen atom between two atoms, to either of which it forms a covalent bond. Since the tautomeric compounds exist in mobile equilibrium with each other they may be regarded as different isomeric forms of the same compound. It is to be understood that the formulae within this specification can represent only one of the possible tautomeric forms. However, it is also to be understood that the disclosure encompasses any tautomeric form, and is not to be limited merely to any one tautomeric form utilized within the formula drawings.
  • Tautomerism can also occur with substituted pyrazoles such as 3-methyl, 5-methyl, or 3,5-dimethylpyrazoles, and the like.
  • Another example of tautomerism is amido-imido (lactam- lactim when cyclic) tautomerism, such as is seen in heterocyclic compounds bearing a ring oxygen atom adjacent to a ring nitrogen atom.
  • the equilibrium: o OH i s an example of tautomerism.
  • a structure depicted herein as one tautomer is intended to also include the other tautomer.
  • Isomers resulting from the presence of a chiral center comprise a pair of non-superimposable isomers that are called “enantiomers.”
  • Single enantiomers of a pure compound are optically active, i.e., they are capable of rotating the plane of plane polarized light.
  • Single enantiomers are designated according to the Cahn-Ingold-Prelog system.
  • the priority of substituents is ranked based on atomic weights, a higher atomic weight, as determined by the systematic procedure, having a higher priority ranking. Once the priority ranking of the four groups is determined, the molecule is oriented so that the lowest ranking group is pointed away from the viewer.
  • the therapeutic preparation may be enriched to provide predominantly one enantiomer of a compound (e.g., of formula (I), (la), or (lb)).
  • An enantiomerically enriched mixture may comprise, for example, at least 60 mol percent of one enantiomer, or more preferably at least 75, 90, 95, or even 99 mol percent.
  • a compound of the disclosure may have greater than 30% ee, 40% ee, 50% ee, 60% ee, 70% ee, 80% ee, 90% ee, or even 95% or greater ee.
  • the compound enriched in one enantiomer is substantially free of the other enantiomer, wherein substantially free means that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture.
  • substantially free means that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture.
  • a composition or compound mixture contains 98 grams of a first enantiomer and 2 grams of a second enantiomer, it would be said to contain 98 mol percent of the first enantiomer and only 2% of the second enantiomer.
  • compounds described herein may have more than one stereocenter.
  • the compounds may be enriched in one or more diastereomer.
  • a compound may have greater than 30% de, 40% de, 50% de, 60% de, 70% de, 80% de, 90% de, or even 95% or greater de.
  • Isolated optical isomers may be purified from racemic mixtures by well-known chiral separation techniques, such as but not limited to, normal and reverse phase chromatography, and crystallization. According to one such method, a racemic mixture of a compound, or a chiral intermediate thereof, is separated using a chiral salt or carried out on a Chiralcell OD column. The column can be operated according to the manufacturer’s instructions.
  • Isolated optical isomers can also be prepared using chiral intermediates or catalysts in synthesis.
  • the optical center chiral center
  • Chiral catalyst can be used to impart at least some degree of enantiomeric purity to products of reactions catalyzed by the chiral catalyst.
  • compounds having at least some degree of enantiomeric enrichment can be obtained by physical processes such as selective crystallization of salts or complexes formed with chiral adjuvants.
  • a variety of compounds may exist in particular geometric or stereoisomeric forms.
  • the present disclosure takes into account all such compounds, including tautomers, cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as being covered within the scope of this disclosure. All tautomeric forms are encompassed in the present disclosure. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this disclosure, unless the stereochemistry or isomeric form is specifically indicated.
  • compounds of Formulae (I)-(IX) have one or more chiral centers and therefore can exist as enantiomers and/or diastereomers.
  • Compounds of Formulae (I)-(IX) may also exist as stereoisomers, for example atropisomers, resulting from hindered rotation about a single bond.
  • the compound of the disclosure are understood to extend to, and embrace all such enantiomers, diastereomers, atropisomers, stereoisomers, and mixtures thereof, including but not limited to racemates.
  • Formulae (I)-(IX) (and the other compounds of the disclosure) used throughout this disclosure are intended to represent all individual stereoisomers and mixtures thereof, unless stated or shown otherwise.
  • the compounds described herein have a particular spatial arrangement of substituents on the aromatic rings, which are related to the structure activity relationship demonstrated by the compound class. Often, such substitution arrangement is denoted by a numbering system; however, numbering systems are often not consistent between different ring systems. In six-membered aromatic systems, the spatial arrangements are specified by the common nomenclature “para” for 1,4-substitution, “meta” for 1,3 -substitution and “ortho” for 1,2-substitution as shown below.
  • the compounds described herein may contain a double bond. It is understood that cis/trans isomers are configurational isomers having different orientation at the double bond. In certain such embodiments, the compounds of this disclosure can be in either cis- or trans- formation. In the present disclosure, the term “cis” is equivalently used for "Z” and vice versa “trans” for'E” and vice versa.
  • Compounds described herein also include all isotopes of atoms occurring in the compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include deuterium and tritium.
  • the term “subject” refers to an animal.
  • the terms “subject” and “patient” may be used interchangeably herein in reference to a subject.
  • the term “subject” includes mammals (e.g ., humans, non-human primates, cows, sheep, goats, horses, dogs, cats, rabbits, guinea pigs, rats, mice, etc.).
  • the subject is a human.
  • the terms “treat,” “treating” and “treatment” refer to the treatment of a patient afflicted with a pathological condition and refers to an effect that alleviates the condition, but also to an effect that results in the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, amelioration of the condition, and cure of the condition. Treatment as a prophylactic measure (i.e., prophylaxis) is also included.
  • “SHMT” refers to serine hydroxymethyltransferase. Such enzymes are known and, in mammals, both SHMT1 and SHMT2 are expressed and active.
  • SHMTs include mammalian SHMT1 and SHMT2, such as human SHMT1 and SHMT2. Further structural information regarding human SHMT1 can be found at NCBI entrez ID number 6470. Further structural information regarding human SHMT2 can be found at NCBI entrez ID number 6472. [00112]
  • SHMT activity is meant a native function of a mammalian SHMT enzyme, such its native enzymatic activity. In certain embodiments, SHMT activity refers to the function of mammalian SHMT to catalyze a reversible reaction converting serine to glycine.
  • SHMT activity refers to the function of mammalian SHMT to catalyze a reversible reaction converting serine to glycine with concurrent methylene- tetrahydrofolate (meTHF) generation.
  • SHMT activity refers to the generation of 1C units.
  • SHMT activity may be assayed or evaluated in numerous ways, such as is described herein.
  • SHMT activity may be evaluated by evaluating serine flux and/or folate metabolism, such as mitochondrial serine flux, glycine synthesis, NADPH generation, generation and excretion of formate or mitochondrial folate metabolism.
  • administering or “administration of’ a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art.
  • a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g, through a skin duct).
  • a compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g.
  • the administration includes both direct administration, including self-administration, and indirect administration, including the act of prescribing a drug.
  • a physician who instructs a patient to self-administer a drug, or to have the drug administered by another and/or who provides a patient with a prescription for a drug is administering the drug to the patient.
  • the disclosure contemplates that the agents may be administered at the same or differing times and via the same or differing routes of administration.
  • Appropriate methods of administering a substance, a compound or an agent to a subject will also depend, for example, on the age of the subject, whether the subject is active or inactive at the time of administering, whether the subject is cognitively impaired at the time of administering, the extent of the impairment, and the chemical and biological properties of the compound or agent (e.g. solubility, digestibility, bioavailability, stability and toxicity).
  • a “therapeutically effective amount” or “effective amount”, used interchangeably herein, refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result. The full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. A therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of a therapeutic or a combination of therapeutics to elicit a desired response in the individual. A skilled worker can readily determine the effective amount for a given situation.
  • the present disclosure generally relates to methods and related compositions for manipulating serine metabolism (e.g., serine catabolism) for treating NADH related disorders, such as, e.g., respiration impairment.
  • serine metabolism e.g., serine catabolism
  • NADH related disorders such as, e.g., respiration impairment.
  • MTHFD2 mitochondrial enzyme
  • Mammals break down carbohydrate, amino acids (glutamine, branch chain amino acids), and fatty acids for the energy generation.
  • TCA tricarboxylic acid
  • NADH is recycled back to its oxidative form NAD+ via mitochondrial complex I, driving high energetic electron to electron transport chain (ETC) for ATP generation.
  • ETC electron transport chain
  • Electrons transferred from NADH to mitochondrial complex I and downstream components of the electron transport chain (ETC) eventually reduce oxygen to water.
  • ETC electron transport chain
  • isocitrate dehydrogenase 1/2 (IDH1/2) prefer to reduce a- ketoglutarate into citrate for a depletion of intracellular citrate level.
  • Glutamine reductive carboxylation becomes the primary acetyl-CoA source for cells in hypoxia or with defective mitochondria. Resulting from a stop of glutamine oxidation in mitochondria, cells are confronted with low abundance of cellular aspartate, whose de novo synthesis is proven to be the essential function of intact ETC.
  • Example causes of NADH elevation include, but are not limited to, mitochondrial electron transport chain deficiency (e.g., inborn error of metabolism, or due to aging or disease); hypoxia/anoxia (e.g., caused by heart attack, stroke, or other ischemic events, or associated with tumor microenvironments), impaired oxygenation due to excessive fat (e.g., in excess of adipose or fatty liver disease); and drug therapy (e.g., metformin treatment or treatment with other electron transport chain inhibitors, like phenformin, rotenone, and antimycin, or treatment with drugs having a side effect of ETC impairment).
  • mitochondrial electron transport chain deficiency e.g., inborn error of metabolism, or due to aging or disease
  • hypoxia/anoxia e.g., caused by heart attack, stroke, or other ischemic events, or associated with tumor microenvironments
  • impaired oxygenation due to excessive fat e.g., in excess of adipose or fatty liver disease
  • a scientific foundation of this disclosure is the observation that serine catabolism becomes a major NADH source when respiration is impaired. This presents the possibility to manipulate NADH for therapeutic purposes via manipulating the serine pathway, for example, through substrate feeding, acceleration, or blockade. One outcome of doing so is improved fitness of animals with genetic deficiencies of the serine pathway. Excess NADH can also be a problem in ischemic diseases like heart attack, stroke, etc. Enhanced NADH likely plays a role in other diseases as well.
  • the disclosure provides methods of treating disorders associated with excess NADH, such as, e.g., respiration impairment, in a subject (e.g., a subject in need thereof), comprising modulating serine metabolism (e.g., modulating serine catabolism) in the subject.
  • modulating comprises inhibiting serine metabolism (e.g., serine catabolism).
  • modulating serine metabolism comprises administering (e.g., a therapeutically effective amount of) a modulator (e.g., inhibitor) of serine metabolism (e.g., serine catabolism) to the subject.
  • the disclosure provides methods of treating disorders associated with excess NADH, such as, e.g., respiration impairment, in a subject (e.g., a subject in need thereof), comprising administering a composition (e.g., a therapeutically effective amount of a composition) to the subject that modulates (e.g., inhibits) serine catabolism.
  • a composition e.g., a therapeutically effective amount of a composition
  • the composition comprises an antifolate. In some embodiments, the composition comprises a compound that inhibits SHMT2, MTHFD2 or a combination thereof. In one embodiment, the compound is KDG112.
  • the disclosure provides methods of treating a disorder associated with excess NADH, such as, e.g., respiration impairment, in a subject (e.g., a subject in need thereof), comprising administering an inhibitor of serine metabolism (e.g., a therapeutically effective amount of an inhibitor of serine metabolism) to the subject.
  • a disorder associated with excess NADH such as, e.g., respiration impairment
  • an inhibitor of serine metabolism e.g., a therapeutically effective amount of an inhibitor of serine metabolism
  • the disorder is respiration impairment.
  • the respiration impairment is caused by a genetic deficiency of the electron transport chain.
  • the respiration impairment is caused by Leigh syndrome.
  • the disorder is caused by hypoxia. In some embodiments, the disorder is caused by an ischemia. In some embodiments, the disorder is caused by a tumor. In some embodiments, the disorder is caused by impaired oxygenation due to excess adipose tissue. In some embodiments, the disorder is caused by an ischemic event.
  • the inhibitor of serine metabolism is an inhibitor of serine catabolism.
  • the inhibitor of serine catabolism comprises an antifolate.
  • the inhibitor of serine catabolism comprises or is a compound that inhibits SHMT (e.g., SHMT1 and/or SHMT2).
  • the inhibitor of serine catabolism comprises or is a compound the inhibits MTHFD2.
  • the inhibitor of serine catabolism comprises a compound that inhibits SHMT2, MTHFD2 or a combination thereof.
  • the inhibitor of serine catabolism is KDG112.
  • the subject is receiving an electron transport chain inhibitor in combination with the inhibitor of serine metabolism (e.g., serine catabolism).
  • the subject has received an electron transport chain inhibitor, such as metformin, phenformin, rotenone or antimycin.
  • an electron transport chain inhibitor such as metformin, phenformin, rotenone or antimycin.
  • the disclosure provides methods of treating a disorder associated with excess NADH, such as, e.g., respiration impairment, in a subject comprising modulating serine metabolism (e.g., serine catabolism) in the subject.
  • a disorder associated with excess NADH such as, e.g., respiration impairment
  • the respiration impairment is caused by a genetic deficiency of the electron transport chain.
  • the respiration impairment is caused by Leigh Syndrome.
  • the modulating comprises inhibition of serine metabolism. In some embodiments, the modulating comprises inhibition of serine catabolism. In one embodiment, the modulating comprises disrupting the mitochondrial folate system.
  • the respiration impairment is caused by hypoxia.
  • the disorder is caused by an ischemia.
  • the disorder is caused by a tumor.
  • the disorder is caused by impaired oxygenation due to excess adipose tissue.
  • the disorder is caused by an ischemic event.
  • the NADH build-up, or excess, in the subject is caused by (or is a side effect of) electron transport chain inhibitors, such as metformin, phenformin, rotenone and/or antimycin.
  • the disclosure provides methods of treating a mitochondrial disorder in a subject (e.g., a subject in need thereof), comprising administering an effective amount of a modulator of serine metabolism (e.g., an inhibitor of serine metabolism) to the subject, wherein the modulator of serine metabolism modulates mitochondrial serine metabolism.
  • a modulator of serine metabolism e.g., an inhibitor of serine metabolism
  • the modulator of serine metabolism is a modulator of serine catabolism.
  • the modulator of serine catabolism is an inhibitor of serine catabolism.
  • the disclosure provides methods of treating a mitochondrial disorder in a subject (e.g., a subject in need thereof), comprising administering a composition that modulates (e.g., inhibits) the mitochondrial serine catabolic pathway.
  • a composition that modulates e.g., inhibits
  • the composition comprises a compound that inhibits SHMT2, MTHFD2 or a combination thereof.
  • the composition comprises the compound KDG112.
  • the disclosure provides methods for treating a disease involving deficient respiration in a subject (e.g., a subject in need thereof), comprising administering a therapeutically effective amount of an inhibitor of serine metabolism (e.g., serine catabolism) to the subject.
  • a subject e.g., a subject in need thereof
  • administering a therapeutically effective amount of an inhibitor of serine metabolism (e.g., serine catabolism) to the subject.
  • the disease is a genetically inherited mitochondrial disorder. In some embodiments, the disease is myocardial infarction or stroke.
  • the inhibitor of serine metabolism is an antifolate.
  • the antifolate is a DHFR inhibitor, mitochondrial folate transporter inhibitor, MTHFD2L or MTHFD1L inhibitor or a combination thereof.
  • the antifolate is methotrexate, pemetrexed, proguanil, pyrimethamine, lometrexol, AG2034, nolatrexed, raltitrexed, talotrexin, plevitrexed, edatrexate, pralatrexate, trimetrexate, piritrexim or trimethoprim, or a combination thereof.
  • the inhibitor of serine metabolism inhibits SHMT (e.g., SHMT1, SHMT2 or SHMT1 and SHMT2)
  • the inhibitor of serine metabolism inhibits SHMT2 or MTHFD2.
  • the inhibitor of SHMT2 or MTHFD2 is a small molecule inhibitor.
  • the inhibitor of SHMT2 is a compound described in U.S. Patent No. 10,077,273B2, the contents of which are incorporated herein by reference.
  • the inhibitor of SHMT2 is a compound described in Mainolfi. N., et al., Shmt inhibitors ami uses thereof.
  • the inhibitor of MTHFD2 is a compound described in PCT/US2016/045086, incorporated herein by reference.
  • the inhibitor of MTHFD2 is a substrate-based inhibitor, such as but not limited to, LY345899.
  • the inhibitor of MTHFD2 is carolacton, as described in Fu. C., et al. The natural product carolacton inhibits folate dependent Cl metabolism by targeting FolD/ MTHFD . Nature Comm. 8, Article No. 1529, 2017, the contents of which are incorporated herein by reference.
  • the inhibitor of MTHFD2 is a substrate-based inhibitor that binds to the THF pocket of MTHFD2. In some embodiments of the various aspects described, the inhibitor of MTHFD2 is a substrate-based inhibitor that binds to the NAD pocket of MTHFD2. In certain embodiments, the MTHFD 1L inhibitor is an inhibitor described in Asai, A., et al., Drug discovery of anticancer drugs targeting methylenetetrahydrofolate dehydrogenase 2. Heliyon 4 17 Dec 2018 - Volume 4, Issue 12, e01021, the contents of which are incorporated herein by reference.
  • the MTHFD2 inhibitor is a compound as described in Ota, M., et al., Sulfonamide derivative having coumarin skeleton. PCT/JP2017/04194, the contents of which are incorporated herein by reference. In some embodiments of the various aspects described, the MTHFD2 inhibitor is a compound as described in Mainolfi N., et al., Caffeine inhibitors of MTHFD2 and uses thereof. PCT/US2016/066666, the contents of which are incorporated herein by reference.
  • the MTHFD2 inhibitor is a compound as described in Eadsforth, T.C., et al., Characterization of 2,4-Diamino-6-oxo-l,6- dihydropyrimidin-5-yl Ureido Based Inhibitors of Trypanosoma brucei FolD and Testing for Antipar asdic Activity. J Med Chem 2015 Oct 22;58(20):7938-48.
  • the MTHFD2 inhibitor is a compound, LY374571, as described in Eadsforth, T.C., et al., Acinetobacter baumannii FolD ligand complexes —potent inhibitors of folate metabolism and a re-evaluation of the structure ofLY374571.
  • LY374571 as described in Eadsforth, T.C., et al., Acinetobacter baumannii FolD ligand complexes —potent inhibitors of folate metabolism and a re-evaluation of the structure ofLY374571.
  • the inhibitor of serine metabolism is an inhibitor of serine synthesis including but not limited to phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1) or phosphoserine phosphatase (PSPH).
  • PHGDH phosphoglycerate dehydrogenase
  • PSAT1 phosphoserine aminotransferase 1
  • PSPH phosphoserine phosphatase
  • the inhibitor of serine metabolism is an inhibitor of serine import to mitochondria, e.g., via SFXN1.
  • the inhibitor of PHGDH is a compound described in Pacold, M.E., et al., A PHGDH inhibitor reveals coordination of serine synthesis and 1 -carbon unit fate. Nat Chem Biol. 2016 Jun; 12(6): 452-458.
  • the inhibitor of PHGDH is a piperazine- 1 -thiourea-based inhibitor of PHGDH, as described in Rhode, J.M., et al. Discovery and optimization of piperazine-l-thiourea-based human phosphoglycerate dehydrogenase inhibitors. Bioorganic & Medicinal Chemistry doi: 10.1016/j.bmc.2018.02.016, the teachings of which are incorporated herein by reference.
  • the inhibitor of PHGDH is AstraZeneca PHGDH inhibitor, CBR 5884, Raze inhibitor, a-ketothioamide inhibitor, PKUMDL-WQ-2101, PKUMDL-WQ-2201, NCT-502 or NCT-503, as described in Ravez, S., et al., Challenges and Opportunities in the Development of Serine Synthetic Pathway Inhibitors for Cancer Therapy. J Med Chem 2017, 60 (4), 1227-1237; Fuller, N.
  • the inhibitor of serine metabolism is an inhibitor targeting SHMT2 downstream enzymes, in one-carbon metabolism including but not limited to 5-FU and gemcitabine.
  • a modulator described herein can be used in combination with one or more other therapies (e.g, one or more other therapeutically active agents, radiation therapy).
  • the agent and the one or more other therapies can be administered to a subject sequentially (in any order) or concurrently, or any combination thereof.
  • the agents can be in separate formulations or the same formulation.
  • the agents can be administered sequentially, as separate formulations.
  • the agent and the one or more other therapies should typically be administered to a subject within an appropriate time frame as determined by a skilled clinician (e.g ., a time sufficient to allow an overlap of the pharmaceutical effects of the therapies).
  • a method described herein further comprises administering to the subject a therapeutically effective amount of an additional therapy (e.g., an additional therapeutic agent, such as an electron transport chain inhibitor).
  • an additional therapy e.g., an additional therapeutic agent, such as an electron transport chain inhibitor.
  • the additional therapy is administered in combination with the original agent or therapy.
  • the methods further comprise administering (e.g., a therapeutically effective amount of) an electron transport chain inhibitor (e.g., metformin, IACS-10759) to the subject, e.g. in combination with a modulator of serine metabolism (e.g., an inhibitor of serine metabolism, an inhibitor of serine catabolism) or serine supplement.
  • an electron transport chain inhibitor e.g., metformin, IACS-10759
  • a modulator of serine metabolism e.g., an inhibitor of serine metabolism, an inhibitor of serine catabolism
  • the electron transport chain inhibitor and the modulator of serine metabolism are administered sequentially.
  • the electron transport chain inhibitor and the modulator of serine metabolism are administered concurrently, e.g., in the same formulation or in separate formulations.
  • the disclosure provides methods of treating a mitochondrial disease by administering to the subject in need thereof compounds that modulate folate-mediated NADH generation separate from serine, including but not limited to, compounds that modulate catabolism of glycine, choline, trimethylglycine (betaine), dimethylglycine, and methylglycine (sarcosine).
  • compounds that modulate folate-mediated NADH generation separate from serine include but are not limited to modulators of dimethylglycine dehydrogenase, sarcosine dehydrogenase or ALDH7A1.
  • the disclosure provides methods of treating a mitochondrial disease wherein the inhibitor of serine metabolism is administered in combination with one or more anti-cancer drugs. In certain embodiments, the disclosure provides methods wherein the inhibitor of serine metabolism is administered in combination with an anti-cancer drug or anti cancer therapy that causes mitochondrial dysfunction.
  • the anti-cancer drugs include but are not limited to monoclonal antibodies against tyrosine kinase receptors, tyrosine kinase inhisbitors, and anti angiogenic drugs.
  • the anti-cancer drugs include drugs related to but not limited to doxorubicin, paclitaxel, cyclophosphamide, ifosfamide, melphalan, chlorambucil, dacarbazine, cisplatin, oxaliplatin, idarubicin, mitoxantrone, etoposide, dexamethasone, tamoxifen, anti-aromatase, anti-androgens, anti estrogens, LH-RH agonists, retinoids or a combination thereof.
  • the anti cancer drug is the compound, deguelin, as described in Wang.
  • the anti-cancer drugs include drugs related to but not limited to doxorubicin, trastazumab or sunitinib or a combination thereof.
  • the disclosure provides methods wherein the inhibitor of serine metabolism is administered in combination with radiation therapy.
  • the disclosure provides methods for treating a mitochondrial disease in a subject (e.g., a subject in need thereof), comprising administering a diet or dietary supplement deficient in serine compared to other amino acids to the subject.
  • the disclosure provides methods of improving the therapeutic index of an electron transport chain inhibitor (e.g, metformin, IACS-10759) in a subject, comprising administering a therapeutically effective amount of an inhibitor of serine metabolism (e.g., an inhibitor of serine catabolism) to the subject, wherein the subject is receiving the electron transport chain inhibitor in combination with the inhibitor of serine metabolism.
  • the methods further comprise administering (e.g., a therapeutically effective amount of) the electron transport chain inhibitor (e.g., metformin, IACS-10759) to the subject.
  • the disclosure provides methods of improving the therapeutic index of metformin in a subject (e.g., a subject in need thereof), comprising administering a therapeutically effective amount of an inhibitor of serine metabolism to the subject.
  • the therapeutic index of a drug is the ratio of the dose of a drug that achieves a predetermined toxicity endpoint (e.g, toxic dose in 50% of subjects, TD 50 ) to the dose of drug that achieves a desired pharmacological effect (e.g ., efficacious dose in 50% of subjects, ED 50 ).
  • a skilled worker can calculate the therapeutic index of a drug.
  • the disclosure provides methods for improving the effectiveness of an electron transport chain inhibitor (e.g., metformin, IACS-10759) in a subject, comprising administering to the subject an effective amount of a serine supplement, wherein the subject is receiving the electron transport chain inhibitor in combination with the serine supplement.
  • the methods further comprise administering (e.g., a therapeutically effective amount of) the electron transport chain inhibitor (e.g., metformin, IACS-10759) to the subject.
  • the disclosure provides methods for improving the effectiveness of metformin in a subject (e.g., a subject in need thereof), comprising administering a serine supplement to the subject.
  • Examples of electron transport chain inhibitors include metformin, phenformin, rotenone, deguelin, antimycin and oligomycin.
  • a further example of an electron transport chain inhibitor is IACS-10759.
  • an electron transport chain inhibitor is metformin, phenformin, rotenone, deguelin, antimycin, oligomycin or a combination thereof.
  • an electron transport chain inhibitor is metformin.
  • an electron transport chain inhibitor is IACS-10759.
  • Serine supplements can contain L-serine and/or D-serine, but typically contain L- serine. Choline or phosphatidylcholine can also be used to provide one-carbon unit supplementation and thereby mimic serine supplementation.
  • the following foods are examples of sources of L-serine that can be used as a serine supplement: eggs, soy protein, fish, bacon and turkey.
  • the disclosure provides methods of treating a tumor in a subject (e.g., a subject in need thereof), comprising administering to the subject an effective amount of an activator of serine catabolism.
  • the method of treating a tumor further comprises administering an electron transport chain inhibitor to the subject.
  • the electron transport chain inhibitor can be, e.g., metformin, phenformin, rotenone, deguelin, antimycin, oligomycin, or a combination thereof.
  • agents, modulators (e.g., inhibitors) and compositions (e.g., compositions) described herein may be carried out in any manner, e.g., by parenteral or nonparenteral administration, including by aerosol inhalation, injection, infusions, ingestion, implantation or transplantation.
  • the agents, modulators and compositions (e.g., compositions) described herein may be administered to a patient trans-arterially, intradermally, subcutaneously, intratumorally, intramedullary, intranodally, intramuscularly, by intravenous (i.v.) injection, or intraperitoneally.
  • oral, dietary, topical, transdermal, rectal, parenteral (e.g., intra-arterial, intravenous, intramuscular, subcutaneous injection, intradermal injection), intravenous infusion and inhalation (e.g, intrabronchial, intranasal or oral inhalation, intranasal drops) routes of administration may all be used, depending, for example, on the agent, inhibitor or composition and the particular disease to be treated. Administration can be local or systemic as indicated.
  • the agent, inhibitor or composition e.g., composition
  • the agent, inhibitor or composition is administered by i.v. injection.
  • the agent, inhibitor or composition is administered to a subject by intradermal or subcutaneous injection.
  • Delivery systems useful in the context of embodiments of the disclosure may include time-released, delayed release, and sustained release delivery systems such that the delivery of the drugs/compounds occurs prior to, and with sufficient time to cause, sensitization of the site to be treated.
  • the composition can be used in conjunction with other therapeutic agents or therapies. Such systems can avoid repeated administrations of the composition, thereby increasing convenience to the subject and the physician, and may be particularly suitable for certain composition embodiments of the disclosure.
  • the modulators of serine metabolism may be provided in suitable pharmaceutical compositions comprising the modulator of serine metabolism and a pharmaceutically acceptable carrier.
  • the carrier may be diluent, adjuvant, excipient, or vehicle with which the modulator (e.g., inhibitor) of serine metabolism is administered.
  • vehicles may be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. For example, 0.4% saline and 0.3% glycine can be used.
  • compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, stabilizing, thickening, lubricating and coloring agents, etc.
  • concentration of the molecules or antibodies of the disclosure in such pharmaceutical formulation may vary widely, i.e., from less than about 0.5%, usually to at least about 1 % to as much as 15 or 20% by weight and will be selected primarily based on required dose, fluid volumes, viscosities, etc., according to the particular mode of administration selected.
  • Suitable vehicles and formulations, inclusive of other human proteins, e.g., human serum albumin, are described, for example, in e.g. Remington: The Science and Practice of Pharmacy, 2P1 Edition, Troy, D.B. ed., Lipincott Williams and Wilkins, Philadelphia, PA 2006, Part 5, Pharmaceutical Manufacturing pp 691-1092, see especially pp. 958-989.
  • Inhibitors e.g., small molecule inhibitors of SHMT, such as inhibitors of SHMT1 and/or SHMT2, and methods of making and using the same, are described in U.S. Patent Application Publication Nos. US 2018/0117010 and US 2018/0072751, the contents of which are incorporated herein by reference in their entireties.
  • SHMT inhibitors e.g., SHMTl and/or SHMT2 inhibitors
  • SHMT inhibitors including any of the SHMT inhibitors described herein, can be used in the methods described herein.
  • a modulator of serine metabolism described herein is a SHMT inhibitor.
  • the SHMT inhibitor is a SHMTl inhibitor.
  • the SHMT inhibitor is a SHMT2 inhibitor.
  • the SHMT inhibitor is a SHMTl inhibitor and a SHMT2 inhibitor.
  • An embodiment of an SHMT inhibitor is a compound of Formula (I):
  • R°, R 1 and R 2 are each independently selected from the group consisting of -H, halogen (such as F, Br, or Cl), hydroxyl, nitro, nitrile, -S0R u ,-S(0) 2 R u , -S(O) 2 NR 10 R 12 , -OR 11 , -0C(0)R 12 , -C(0)0R 12 , -C(0)R u , -C(O)NR 10 R 12 , -NR 10 R 12 , -N(R 12 )C(0)R u , -NS(0) 2 R 12 , substituted or unsubstituted alkyl (such as C C 8 alkyl or Ci-C 6 alkyl; e.g., methyl, ethyl, or iso propyl), substituted or unsubstituted alkenyl (such as C 2 -C 8 alkenyl), substituted or unsubstituted alkynyl (such as C 2
  • R 3 is selected from the group consisting of -H, halogen, hydroxyl, nitro, nitrile, -SOR 11 , - S(0) 2 R u , -S(0) 2 NR 10 R 12 , -OR 11 , -0C(0)R 12 , -C(0)0R 12 , -C(0)R u , -C(O)NR 10 R 12 , - NR 10 R 12 , -N(R 12 )C(0)R u , -NS(0) 2 R 12 , substituted or unsubstituted alkyl (such as C C 8 alkyl or Ci-C 6 alkyl; e.g., methyl, ethyl, or iso-propyl), substituted or unsubstituted cycloalkyl (such as C3-C7 cycloalkyl; e.g., cyclopropyl or cyclobutyl), substituted or unsubstituted heterocyclyl,
  • R 4 is selected from the group consisting of -H, substituted or unsubstituted alkyl (such as C r C 8 alkyl; e.g., methyl, ethyl, or iso-propyl), substituted or unsubstituted cycloalkyl (such as C3-C7 cycloalkyl; e.g., cyclopropyl or cyclobutyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, and substituted or unsubstituted heteroarylalkyl;
  • substituted or unsubstituted alkyl such as C r C 8 alkyl; e.g., methyl, ethyl, or iso-propyl
  • substituted or unsubstituted cycloalkyl such as C3-C7 cycloalkyl; e.g.,
  • R 5 , R 6 and R 7 are each independently selected from the group consisting of -H, -C(0)R u , substituted or unsubstituted alkyl (such as Ci-C 8 alkyl or Ci-C 6 alkyl; e.g., methyl, ethyl, or iso-propyl), substituted or unsubstituted cycloalkyl (such as C3-C7 cycloalkyl; e.g., cyclopropyl or cyclobutyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, and substituted or unsubstituted heteroarylalkyl; or R 5 is selected from any of the foregoing and R 6 and R 7 taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted 3-6 membered ring; each occurrence of R 11 is independently selected
  • an SHMT inhibitor is represented by Formula (la): pharmaceutically acceptable salt there.
  • an SHMT inhibitor is represented by Formula (lb): pharmaceutically acceptable salt thereof.
  • R°, R 1 and R 2 are each independently selected from the group consisting of -H, halogen, hydroxyl, nitro, nitrile, -SOR 11 , -S(0) 2 R u , -S(0) 2 NR 10 R 12 , -OR 11 , -C(0)OR 12 , -C(0)R u , -C(O)NR 10 R 12 , -NR 10 R 12 , -
  • N(R 12 )C(0)R u , -NS(0) 2 R 12 substituted or unsubstituted alkyl (such as Ci-C 8 alkyl or Ci-C 6 alkyl; e.g., methyl, ethyl, or iso-propyl), substituted or unsubstituted alkenyl (such as C 2 -C 8 alkenyl), substituted or unsubstituted alkynyl (such as C 2 -C 8 alkynyl), substituted or unsubstituted cycloalkyl (such as C3-C7 cycloalkyl; e.g., cyclopropyl or cyclobutyl), substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted
  • one of R 1 and R 2 is selected from the group consisting of substituted or unsubstituted alkenyl (such as C 2 -C 8 alkenyl), and substituted or unsubstituted alkynyl (such as C 2 -C 8 alkynyl); the other is independently selected from the group consisting of -H, halogen, hydroxyl, nitro, nitrile, -SOR 11 , -S(0) 2 R u , -S(0) 2 NR 10 R 12 , -OR 11 , -C(0)0R 12 , -C(0)R u , -C(O)NR 10 R 12 , -NR 10 R 12 , - N(R 12 )C(0)R u , -NS(0) 2 R 12 , substituted or unsubstituted alkyl (such as Ci-C 8 alkyl or Ci-C 6 alkyl; e.g.,
  • one of R 1 and R 2 is selected from the group consisting of substituted or unsubstituted alkenyl (such as C 2 -C 8 alkenyl), and substituted or unsubstituted alkynyl (such as C 2 -C 8 alkynyl); the other is independently selected from the group consisting of -H, halogen, hydroxyl, nitro, nitrile, -OR 11 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl (such as Ci-C 8 haloalkyl or Ci-C 6 haloalkyl; e.g., trifluoromethyl), and substituted or unsubstituted haloalkoxy (such as C C 8 haloalkoxy or Ci-C 6 haloalkyl
  • one of R 1 and R 2 is substituted or unsubstituted alkynyl (such as C 2 -C 8 alkynyl), the other is not. In other embodiments, both R 1 and R 2 are substituted or unsubstituted alkynyl (such as C 2 -C 8 alkynyl). [00175] In some embodiments of any of the foregoing or following, one of R 1 and R 2 is substituted or unsubstituted alkenyl (such as C 2 -C 8 alkenyl), the other is not.
  • both R 1 and R 2 are substituted or unsubstituted alkenyl (such as C 2 -C 8 alkenyl).
  • R 1 is substituted or unsubstituted alkynyl and R 2 is not a substituted or unsubstituted alkynyl (such as C 2 -C 8 alkynyl).
  • R 2 is substituted or unsubstituted alkynyl and R 1 is not a substituted or unsubstituted alkynyl (such as C 2 -C 8 alkynyl).
  • R 1 is substituted or unsubstituted alkenyl and R 2 is not a substituted or unsubstituted alkenyl (such as C 2 -C 8 alkenyl).
  • R 2 is substituted or unsubstituted alkenyl and R 1 is not a substituted or unsubstituted alkenyl (such as C 2 -C 8 alkenyl).
  • the alkenyl (such as C 2 - C 8 alkenyl) or alkynyl (such as C 2 -C 8 alkynyl), when substituted, is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, nitro, nitrile, -SOR 11 , -S(0) 2 R u , -S(0) 2 NR 10 R 12 , -OR 11 , -OC(0)R 12 , -C(0)OR 12 , -C(0)R u , -C(O)NR 10 R 12 , - NR'°R 12 , -N(R 12 )C(0)R u , -NS(0) 2 R 12 , optionally substituted aryl, and optionally substituted heteroaryl comprising 1-4 N atoms; or two of the substituents together with the atoms to which they are attached form an optionally substituted ring.
  • substituents independently selected from the group consisting of halogen,
  • alkenyl such as C 2 -C 8 alkenyl
  • alkynyl such as C 2 -C 8 alkynyl
  • substituents independently selected from the group consisting of OH, halogen, -OR 11 , - C(0)OR 12 , -C(O)NR 10 R 12 , -NR 10 R 12 , optionally substituted aryl, and optionally substituted heteroaryl comprising 1-4 N atoms; or two of the substituents together with the atoms to which they are attached form an optionally substituted ring.
  • R° is selected from the group consisting of hydroxyl, -S(0) 2 R u , -S(O) 2 NR 10 R 12 , -OR 11 , -C(O)NR 10 R 12 , -NR 10 R 12 - N(R 12 )C(0)R u , and -NS(0) 2 R 12 .
  • R° is H.
  • R 3 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, cyclopropyl, and cyclobutyl. In certain such embodiments, R 3 is selected from the group consisting of isopropyl, cyclopropyl, and cyclobutyl. In some embodiments, R 3 is isopropyl.
  • R 4 is selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and benzyl. In certain such embodiments, R 4 is methyl or isopropyl. In some embodiments, R 4 is methyl.
  • R 5 , R 6 , and R 7 are each independently selected from the group consisting of -H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, and -COCH 3 .
  • R 5 , R 6 and R 7 are each independently selected from the group consisting of -H, methyl, phenyl, and -COCH 3.
  • R 5 and R 6 are each independently selected from the group consisting of -H, methyl, and phenyl.
  • R 7 is -H.
  • R 5 is selected from the group consisting of -H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, and -COCH 3 ; and R 6 and R 7 taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted ring selected from the group consisting of:
  • R 5 is selected from the group consisting of -H, methyl, phenyl, and -COCH 3 ; and R 6 and R 7 taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted ring selected from the group consisting of:
  • R° is selected from the group consisting of -H, halogen, hydroxyl, nitro, nitrile, -S(0) 2 R u , -S(O) 2 NR 10 R 12 , -OR 11 , - C(O)NR 10 R 12 , -NR 10 R 12 , -N(R 12 )C(0)R u , -NS(0) 2 R 12 , substituted or unsubstituted alkyl (such as Ci-Cg alkyl; e.g., methyl, ethyl, or iso-propyl), substituted or unsubstituted cycloalkyl (such as C 3 -C 7 cycloalkyl; e.g., cyclopropyl or cyclobutyl), substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted
  • R 3 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, cyclopropyl, and cyclobutyl;
  • R 4 is selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and benzyl;
  • R 5 , R 6 and R 7 are each independently selected from the group consisting of -H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, and -COCH 3.
  • R° is -H; one of R 1 and R 2 is substituted or unsubstituted alkenyl (such as C 2 -C 8 alkenyl), or substituted or unsubstituted alkynyl (such as C 2 -C 8 alkenyl); the other is independently selected from the group consisting of -H, halogen, hydroxyl, nitro, nitrile, -OR 11 , substituted or unsubstituted alkyl (such as C C 8 alkyl Ci-C 6 alkyl); e.g., methyl, ethyl, or iso-propyl), substituted or unsubstituted alkenyl (such as C 2 -C 8 alkenyl), substituted or unsubstituted alkynyl (such as C 2 -C 8 alkynyl), substituted or unsubstituted haloalkyl (such as Ci-C
  • R 3 is selected from the group consisting of isopropyl, cyclopropyl, and cyclobutyl;
  • R 4 is methyl or isopropyl
  • R 5 , R 6 and R 7 are each independently selected from the group consisting of -H, alkyl (such as Ci-Cg alkyl Ci-C 6 alkyl); e.g., methyl, ethyl, or iso-propyl), phenyl, and -COCH 3 .
  • R° is -H; one of R 1 and R 2 is substituted or unsubstituted alkenyl (such as C 2 -C 8 alkenyl), or substituted or unsubstituted alkynyl (such as C 2 -C 8 alkynyl); the other is independently selected from the group consisting of -H, methoxy, fluoro, chloro, bromo, hydroxyl, nitro, nitrile, alkyl, - CC1 3 , and -CF 3 ;
  • R 3 is cyclobutyl or iso-propyl
  • R 4 is methyl
  • R 5 and R 6 are each independently selected from the group consisting of -H, alkyl (such as Ci-C 6 alkyl; e.g., methyl, ethyl, or iso-propyl), and phenyl; and
  • R 7 is H.
  • R° is selected from the group consisting of -H, hydroxyl, -S(0) 2 R u , -S(O) 2 NR 10 R 12 , -OR 11 , -C(O)NR 10 R 12 , -NR 10 R 12 , - N(R 12 )C(0)R u , and -NS(0) 2 R 12 ; one of R 1 and R 2 is substituted or unsubstituted alkynyl (such as C 2 -C 8 alkynyl); the other is nitro, -Cl, -OCH 3 , or -CF 3 ; R 3 is iso-propyl; R 4 is methyl; and R 5 , R 6 , and R 7 are H.
  • an SHMT inhibitor is a compound of Formula (II): or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as defined herein;
  • R 13 , R 14 , and R 15 are independently selected from the group consisting of hydrogen, -OH, halogen, optionally substituted alkyl (such as Ci-C 8 alkyl or Ci-C 6 alkyl); e.g., methyl, ethyl, or iso-propyl), optionally substituted haloalkyl (such as C C 8 haloalkyl or Ci-C 6 haloalkyl; e.g., trifluoromethyl), -OR a , -OC(0)R b , -C(0)NR a R b , and -NR a R b ; or R 13 and R 14 together with the atom to which they are attached form a 4-7 membered heterocyclic ring comprising 1 or 2 heteroatoms selected from the group consisting of NR a , O, S, or SO, or S0 2
  • the compound of Formula (II) can be represented by
  • R 13 , R 14 , and R 15 are independently selected from the group consisting of hydrogen, -OH, halogen, optionally substituted alkyl (such as Ci.C 8 alkyl or Ci-C 6 alkyl; e.g., methyl, ethyl, or iso-propyl), optionally substituted haloalkyl (such as Ci-C 8 haloalkyl or Ci-C 6 haloalkyl; e.g., trifluoromethyl), -OR a , - 0C(0)R b , -C(0)NR a R b , and -NR a R b , and wherein R a and R b , independently at each occurrence, are H or optionally substituted alkyl ((such as Ci-C 8 alkyl or Ci-C 6 alkyl; e.g., methyl, ethyl, or iso-propyl
  • optionally substituted alkyl such as Ci.C 8 alky
  • n is 0; R 13 and R 14 together with the atom to which they are attached form a 4-7 membered heterocyclic ring comprising 1 or 2 heteroatoms selected from the group consisting of NR a , and O; wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of oxo and optionally substituted alkyl; and R 15 is H.
  • the SHMT inhibitor is a compound of Formula (III): pharmaceutically acceptable salt thereof, wherein
  • R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as defined herein;
  • R 16 is H or optionally substituted alkyl (such as Ci-Cg alkyl or Ci-C 6 alkyl; e.g., methyl, ethyl, or iso-propyl); and
  • A represents optionally substituted aryl or optionally substituted heteroaryl.
  • the compound of Formula (III) can be represented by Formula (Ilia) or (Illb): or a pharmaceutically acceptable salt thereof.
  • W is .
  • A is aryl, optionally substituted with one or more substituents independently selected from the group consisting of - OH, halogen, optionally substituted alkyl (such as C 1 -C 9 alkyl or Ci-C 6 alkyl; e.g., methyl, ethyl, or iso-propyl), optionally substituted haloalkyl (such as C C 8 haloalkyl or Ci-C 6 haloalkyl; e.g., trifluoromethyl), -OR a , -OC(0)R b , -C(0)NR a R b , and -NR a R b , and wherein R a and R b , independently at each occurrence, are H or optionally substituted alkyl.
  • substituents independently selected from the group consisting of - OH, halogen, optionally substituted alkyl (such as C 1 -C 9 alkyl or Ci-C 6 alkyl; e.g.
  • A is phenyl, optionally substituted with one or more substituents independently selected from the group consisting of -CH 2 OH, -OH, -CF 3 ,-COOH, -F, -CH 2 NH 2 , -CONH 2 , and - NH 2 .
  • A is heteroaryl, optionally substituted with one or more substituents independently selected from the group consisting of -OH, halogen, optionally substituted alkyl (such as C C 8 alkyl or Ci-C 6 alkyl; e.g., methyl, ethyl, or iso-propyl), optionally substituted haloalkyl (such as C C 8 haloalkyl or Ci-C 6 haloalkyl; e.g., trifluoromethyl), -OR a , -OC(0)R b , -C(0)NR a R b , and -NR a R b , and wherein R a and R b , independently at each occurrence, are H or optionally substituted alkyl (such as Ci-C 8 alkyl or Ci-C 6 alkyl; e.g., methyl, ethyl, or iso-propyl).
  • substituents independently selected from the group consisting of -OH,
  • A is an optionally substituted heteroaryl containing 1-4 N atoms.
  • A is an optionally substituted tetrazolyl or optionally substituted triazolyl.
  • A is pyridinyl, optionally substituted with one or more substituents independently selected from the group consisting of -H, -CH 2 OH, -OH, -CF 3 ,-COOH, -F, -CH 2 NH 2 , -CONH 2 , and -NH 2
  • R 2 is nitro, -F, -Cl, - OCH 3 , CC1 3 , or -CF 3 _R 3 is selected from the group consisting of isopropyl, cyclopropyl, and cyclobutyl;
  • R 4 is methyl or isopropyl; and
  • R 5 , R 6 and R 7 are each independently selected from the group consisting of -H, alkyl (such as Ci-C 8 alkyl or Ci-C 6 alkyl; e.g., methyl, ethyl, or is
  • an SHMT inhibitor is a compound of Formula (IF): or a pharmaceutically acceptable salt thereof, wherein:
  • R 2 and R 3 are each independently selected for each occurrence from the group consisting of -H, halogen (such as F, Br, or Cl), hydroxyl, nitro, nitrile, -S0R U ,-S(0) 2 R U , -S(O) 2 NR 10 R 12 , - OR 11 , -0C(0)R 12 , -C(0)0R 12 , -C(0)R u , -C(O)NR 10 R 12 , -NR 10 R 12 , -N(R 12 )C(0)R u , - NS(0) 2 R 12 , substituted or unsubstituted alkyl (such as Ci-C 8 alkyl or Ci-C 6 alkyl; e.g., methyl, ethyl, or iso-propyl), substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl
  • R 4 is selected from the group consisting of -H, substituted or unsubstituted alkyl (such as C r C 8 alkyl; e.g., methyl, ethyl, or iso-propyl), substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl (such as C3-C7 cycloalkyl; e.g., cyclopropyl or cyclobutyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, and substituted or unsubstituted heteroarylalkyl;
  • substituted or unsubstituted alkyl such as C r C 8 alkyl; e.g., methyl, ethyl, or iso-propyl
  • R 5 , R 6 and R 7 are each independently selected from the group consisting of -H, -C(0)R u , substituted or unsubstituted alkyl (such as C r C 8 alkyl or Ci-C 6 alkyl; e.g., methyl, ethyl, or iso-propyl), substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl (such as C 3 -C 7 cycloalkyl; e.g., cyclopropyl or cyclobutyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, and substituted or unsubstituted heteroarylalkyl; or R 5 is selected from any of the foregoing and R 6 and R 7 taken together with the nitrogen atom to which they
  • R 16 is H or optionally substituted alkyl (such as C C 8 alkyl or Ci-C 6 alkyl; e.g., methyl, ethyl, or iso-propyl); and
  • L is selected from the group consisting of -H, substituted or unsubstituted alkyl (such as C 1 -C 12 alkyl or C r C 8 alkyl; e.g., methyl, ethyl, iso-propyl, n-butyl, or n-proypl), substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl (such as C 3 -C 7 cycloalkyl; e.g., cyclopropyl or cyclobutyl), substituted or unsubstituted heterocyclyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl.
  • alkyl such as C 1 -C 12 alkyl or C r C 8 alkyl; e.g., methyl, ethyl, iso
  • the compound of Formula (IF) can be represented by Formula (Ha’) or (lib’):
  • L is alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, nitro, nitrile, -SOR u ,-S(0) 2 R u , -S(O) 2 NR 10 R 12 , -OR 11 , -OC(0)R 12 , -C(0)OR 12 , - C(0)R u , -C(O)NR 10 R 12 , -NR 10 R 12 , -N(R 12 )C(0)R u , -NS(0) 2 R 12 , substituted or unsubstituted alkyl (such as Ci-Ci 2 alkyl or Ci-C 8 alkyl; e.g., methyl, ethyl, iso-propyl, or n-butyl), substituted or unsubstituted cycloalkyl (such as C 3 -C 7 cycloal
  • L is alkyl optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, -OH, halogen, optionally substituted alkyl (such as Ci.C i2 alkyl or C C 8 alkyl; e.g., methyl, ethyl, iso-propyl, n-butyl), substituted or unsubstituted heteroaryl, optionally substituted haloalkyl (such as Ci-C 8 haloalkyl or Ci-C 6 haloalkyl; e.g., trifluoromethyl), -OR 11 , -OC(0)R 12 , - C(0)OR 12 , -C(0)R u , -C(O)NR 10 R 12 , -NR 10 R 12 , -N(R 12 )C(0)R u , -NS(0) 2 R 12 .
  • substituents independently selected from the group consisting of hydrogen, -OH, halogen, optionally substituted alky
  • L is cycloalkyl or heterocyclyl ring, optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, nitro, nitrile, -SOR u ,-S(0) 2 R u , -S(O) 2 NR 10 R 12 , -OR 11 , - 0C(0)R 12 , -C(0)0R 12 , -C(0)R u , -C(O)NR 10 R 12 , -NR 10 R 12 , -N(R 12 )C(0)R u , -NS(0) 2 R 12 , substituted or unsubstituted alkyl, and oxo.
  • L is a four to seven membered heterocyclyl ring comprising one to three heteroatoms selected from the group consisting of NR 10 , O, S, SO, or S0 2.
  • L is H.
  • an SHMT inhibitor is a compound of Formula (IIF): pharmaceutically acceptable salt thereof, wherein:
  • R 2 and R 3 are each independently selected for each occurrence from the group consisting of -H, halogen (such as F, Br, or Cl), hydroxyl, nitro, nitrile, -S0R U ,-S(0) 2 R U , -S(O) 2 NR 10 R 12 , - OR 11 , -0C(0)R 12 , -C(0)0R 12 , -C(0)R u , -C(O)NR 10 R 12 , -NR 10 R 12 , -N(R 12 )C(0)R u , - NS(0) 2 R 12 , substituted or unsubstituted alkyl (such as C C 8 alkyl or C r C alkyl; e.g., methyl, ethyl, or iso-propyl), substituted or unsubstituted cycloalkyl (such as C 3 -C 7 cycloalkyl; e.g., cyclopropyl or
  • R 4 is selected from the group consisting of -H, substituted or unsubstituted alkyl (such as C r C 8 alkyl; e.g., methyl, ethyl, or iso-propyl), substituted or unsubstituted cycloalkyl (such as C3-C7 cycloalkyl; e.g., cyclopropyl or cyclobutyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, and substituted or unsubstituted heteroarylalkyl;
  • substituted or unsubstituted alkyl such as C r C 8 alkyl; e.g., methyl, ethyl, or iso-propyl
  • substituted or unsubstituted cycloalkyl such as C3-C7 cycloalkyl; e.g.,
  • R 5 , R 6 and R 7 are each independently selected from the group consisting of -H, -C(0)R u , substituted or unsubstituted alkyl (such as C C 8 alkyl or Ci-C 6 alkyl; e.g., methyl, ethyl, or iso-propyl), substituted or unsubstituted cycloalkyl (such as C3-C7 cycloalkyl; e.g., cyclopropyl or cyclobutyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, and substituted or unsubstituted heteroarylalkyl; or R 5 is selected from any of the foregoing and R 6 and R 7 taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted 3-6 membered ring; each occurrence of R 11 is independently selected from
  • R 16 is H or optionally substituted alkyl (such as Ci-C 8 alkyl or Ci-C 6 alkyl; e.g., methyl, ethyl, or iso-propyl); and
  • A represents optionally substituted aryl or optionally substituted heteroaryl.
  • the compound of Formula (III) can be represented by
  • A is aryl, optionally substituted with one or more substituents independently selected from the group consisting of halogen (such as F, Br, or Cl), hydroxyl, nitro, nitrile, -SOR u ,-S(0) 2 R u , -S(O) 2 NR 10 R 12 , -OR 11 , -OC(0)R 12 , -C(0)OR 12 , -C(0)R u , -C(O)NR 10 R 12 , -NR 10 R 12 , -N(R 12 )C(0)R u , -NS(0) 2 R 12 , substituted or unsubstituted alkyl (such as C C 8 alkyl or Ci-C 6 alkyl; e.g., methyl, ethyl, or iso propyl), substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl
  • A is phenyl, optionally substituted with one or more substituents independently selected from the group consisting of -CH 2 OH, -OH, -CF 3 ,-COOH, -
  • A is heteroaryl, optionally substituted with one or more substituents independently selected from the group consisting of halogen (such as F, Br, or Cl), hydroxyl, nitro, nitrile, -S0R u ,-S(0) 2 R u , - S(O) 2 NR 10 R 12 , -OR 11 , -0C(0)R 12 , -C(0)0R 12 , -C(0)R u , -C(O)NR 10 R 12 , -NR 10 R 12 , - N(R 12 )C(0)R u , -NS(0) 2 R 12 , substituted or unsubstituted alkyl (such as C r C 8 alkyl or Ci-C 6 alkyl; e.g., methyl, ethyl, or iso-propyl), substituted or unsubstituted alkenyl, substituted or unsubstitute
  • A is heteroaryl, optionally substituted with one or more substituents independently selected from the group consisting of -OH, halogen, optionally substituted alkyl (such as Ci-C 8 alkyl or Ci-C 6 alkyl; e.g., methyl, ethyl, or iso-propyl), optionally substituted haloalkyl (such as C C 8 haloalkyl or Ci-C 6 haloalkyl; e.g., trifluoromethyl), -S0R u ,-S(0) 2 R u , -S(O) 2 NR 10 R 12 , -OR 11 , -0C(0)R 12 , - C(0)0R 12 , -C(0)R u , -C(O)NR 10 R 12 , -NR 10 R 12 , -N(R 12 )C(0)R u , -NS(0) 2 R 12 ,
  • substituents independently selected from the group consisting of -OH,
  • A is an optionally substituted heteroaryl containing 1-4 N atoms.
  • A is an optionally substituted tetrazolyl or optionally substituted triazolyl.
  • A is pyridinyl, optionally substituted with one or more substituents independently selected from the group consisting of -H, -CH 2 OH, -OH, -CF 3 ,-COOH, -F, -CH 2 NH 2 , -CONH 2 , and -NH 2
  • R 2 is nitro, -F, -Cl, - OCH 3 , CCI 3 , or -CF 3 _R 3 is selected from the group consisting of isopropyl, cyclopropyl, and cyclobutyl;
  • R 4 is methyl or isopropyl; and
  • R 5 , R 6 and R 7 are each independently selected from the group consisting of -H, alkyl (such as C C 8 alkyl or Ci-C 6 alkyl; e.g., methyl, ethyl, or iso
  • R 2 is -CF 3 ;
  • R 3 is iso propyl;
  • R 4 is methyl; and
  • R 5 , R 6 , and R 7 are H.
  • the SHMT inhibitor is selected from a compound in Table 1, or a pharmaceutically acceptable salt thereof.
  • Table 1 l,4-dihydropyrano[2,3-c]pyrazole derivatives as SHMT inhibitors
  • an SHMT inhibitor is a compound of Formula IV:
  • R°, R 1 and R 2 are each independently selected from -H, halogen, hydroxyl, nitro, nitrile, - SOR 11 , -S(0) 2 R u , -S(0) 2 NR 10 R 12 , -OR 11 , -0C(0)R 12 , -C(0)0R 12 , -C(0)R n , -C(O)NR 10 R 12 , - NR I0 R 12 , -N(R 12 )C(0)R u , -NS(0) 2 R 12 , substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstitute
  • R 3 is selected from-H, halogen, hydroxyl, nitro, nitrile, -SOR 11 , -S(0) 2 R u , - S(O) 2 NR 10 R 12 , -OR 11 , -0C(0)R 12 , -C(0)0R 12 , -C(0)R u , -C(O)NR 10 R 12 , -NR 10 R 12 , - N(R 12 )C(0)R u , -NS(0) 2 R 12 , substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted Ci-C 6 haloal
  • R 4 is selected from H, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted heteroarylalkyl;
  • R 5 , R 6 and R 7 are each independently selected from -H, -C(0)R u , substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted heteroarylalkyl, or R 5 is selected from any of the foregoing and R 6 and R 7 taken together with the nitrogen atom to which they are attached form a substitute
  • the compound of Formula (IV) is represented by Formula (IVa) (wherein the R groups are as described above for Formula (IV):
  • the compound of Formula (IV) is represented by Formula (IVb) (wherein the R groups are as described above for Formula (IV)):
  • R°, R 1 and R 2 are each independently selected from -H, halogen, hydroxyl, nitro, nitrile, -SOR 11 , -S(0) 2 R u , - S(O) 2 NR 10 R 12 , -OR 11 , -C(0)0R 12 , -C(0)R u , -C(O)NR 10 R 12 , -NR 10 R 12 , -N(R 12 )C(0)R u , - NS(0) 2 R 12 , substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroarylalkyl,
  • R° is selected from hydroxyl, -S(0) 2 R u , -S(O) 2 NR 10 R 12 , -OR 11 , -C(O)NR 10 R 12 , -NR 10 R 12 , -N(R 12 )C(0)R u , or -
  • R° is selected from -H, halogen, substituted or unsubstituted Ci-C 6 haloalkyl, substituted or unsubstituted Ci-C 6 haloalkoxy, or substituted or unsubstituted Ci-C 6 alkyl. In other embodiments R° is -H.
  • R 1 and R 2 are each independently selected from -H, halogen, hydroxyl, nitro, nitrile, -OR 11 , substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted Ci-C 6 haloalkyl, or substituted or unsubstituted Ci-C 6 haloalkoxy.
  • R 1 and R 2 are each independently selected from -H, halogen, substituted or unsubstituted Ci-C 6 haloalkyl, substituted or unsubstituted Ci-C 6 haloalkoxy, or substituted or unsubstituted Ci-C 6 alkyl.
  • R 1 and R 2 are each independently selected from -H, methoxy, fluoro, chloro, bromo, hydroxyl, nitro, nitrile, methyl, trifluoromethyl, or trifluorom ethoxy.
  • R° is selected from -H, halogen, substituted or unsubstituted Ci-C 6 haloalkyl, substituted or unsubstituted Ci-C 6 haloalkoxy, or substituted or unsubstituted Ci-C 6 alkyl.
  • R° is -H.
  • R 1 and R 2 are each independently selected from -H, methoxy, chloro, nitro, nitrile, or trifluoromethyl.
  • R° is selected from -H, halogen, substituted or unsubstituted C r C haloalkyl, substituted or unsubstituted Ci-C 6 haloalkoxy, or substituted or unsubstituted C r C alkyl.
  • R° is -H.
  • R 1 and R 2 are each trifluoromethyl.
  • R° is selected from -H, halogen, substituted or unsubstituted Ci-C 6 haloalkyl, substituted or unsubstituted Ci-C 6 haloalkoxy, or substituted or unsubstituted Ci-C 6 alkyl.
  • R° is -H.
  • R 3 is selected from -H, halogen, hydroxyl, nitro, nitrile, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 3 is selected from substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 3 is selected from substituted or unsubstituted Ci-C 6 alkyl, or substituted or unsubstituted cycloalkyl.
  • R 3 is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl. In certain embodiments, any of the foregoing may be optionally substituted.
  • R 3 is selected from isopropyl, cyclopropyl, or cyclobutyl. In certain embodiments, any of the foregoing may be optionally substituted.
  • R 3 is cyclobutyl.
  • acyclobutyl may be optionally substituted.
  • R 4 is selected from -H, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted arylalkyl.
  • R 4 is selected from -H, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted arylalkyl.
  • R 4 is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or benzyl. In certain embodiments, any of the foregoing may be optionally substituted.
  • R 4 is methyl or isopropyl. In certain embodiments, any of the foregoing may be optionally substituted.
  • R 4 is methyl. In certain embodiments, methyl may be optionally substituted.
  • R 5 , R 6 and R 7 are each independently selected from -H, -C(0)R u , substituted or unsubstituted C r C alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, or R 5 is selected from any of the foregoing and R 6 and R 7 taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted 3-6 membered ring.
  • R 5 , R 6 and R 7 are each independently selected from -H, -C(0)R u , substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted arylalkyl.
  • R 5 , R 6 and R 7 are each independently selected from -H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, or -COCH 3.
  • any of the foregoing, except - H, may be optionally substituted.
  • R 5 , R 6 and R 7 are each independently selected from -H, methyl, phenyl, or -COCH 3. In certain embodiments, any of the foregoing, except -H, may be optionally substituted.
  • R 5 and R 6 are each independently selected from -H, methyl or phenyl. In certain embodiments, any of the foregoing, except -H, may be optionally substituted.
  • R 7 is -H.
  • R 6 and R 7 taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted 3- 6 membered ring.
  • the 3-6 membered ring is a monocylic ring.
  • the 3-6 membered ring may be saturated or unsaturated (e.g., contain at least one double bond).
  • the 3-6 membered ring may contain one or two additional heteroatoms, other than the nitrogen atom to which R 6 and R 7 are attached.
  • R 5 is selected from -H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, or - COCH 3 , and R 6 and R 7 taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted ring selected from: [00255] In certain embodiments of any of the foregoing or following, R 5 is selected from -H, methyl, phenyl, or -COCH 3 , and R 6 and R 7 taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted ring selected from:
  • each occurrence of R 11 is independently selected from substituted or unsubstituted Ci-C 6 alkyl or substituted or unsubstituted cycloalkyl. In certain embodiments, there is no occurrence of R 11 .
  • each occurrence of R 10 and R 12 is each independently selected from -H, substituted or unsubstituted Ci-C 6 alkyl, or substituted or unsubstituted cycloalkyl, such as from -H, or substituted or unsubstituted Ci-C 6 alkyl.
  • each occurrence of R 10 and R 12 is -H. In certain embodiments, there is no occurrence of R 10 and/or R 12 .
  • R° is selected from -H, halogen, hydroxyl, nitro, nitrile, -S(0) 2 R u , -S(O) 2 NR 10 R 12 , -OR 11 , -C(O)NR 10 R 12 , -NR 10 R 12 , - N(R 12 )C(0)R u , -NS(0) 2 R 12 , substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted Ci-C 6 haloalkyl, or substituted or unsubstituted Ci-C 6 haloalkyl, or substituted or unsubstitute
  • R 1 and R 2 are each independently selected from -H, methoxy, fluoro, chloro, bromo, hydroxyl, nitro, nitrile, methyl, or trifluoromethyl;
  • R 3 is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl;
  • R 4 is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or benzyl;
  • R 5 , R 6 and R 7 are each independently selected from -H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, or -COCH 3 .
  • R° is selected from -H, hydroxyl, -S(0) 2 R u , -S(O) 2 NR 10 R 12 , -OR 11 , -C(O)NR 10 R 12 , -NR 10 R 12 , -N(R 12 )C(0)R u , or - NS(0) 2 R 12 ;
  • R 1 and R 2 are each independently selected from -H, methoxy, chloro, nitro, nitrile, or trifluorom ethyl;
  • R 3 is selected from isopropyl, cyclopropyl, or cyclobutyl
  • R 4 is methyl or isopropyl
  • R 5 , R 6 and R 7 are each independently selected from -H, methyl, phenyl, or -COCH 3 .
  • R° is selected from -H, hydroxyl, -S(0) 2 R u , -S(O) 2 NR 10 R 12 , -OR 11 , -C(O)NR 10 R 12 , -NR 10 R 12 , -N(R 12 )C(0)R u , or - NS(0) 2 R 12 ;
  • R 1 and R 2 are each -CF 3 ;
  • R 3 is cyclobutyl
  • R 4 is methyl
  • R 5 and R 6 are each independently selected from H, methyl or phenyl; and R 7 is H.
  • the compound is selected from the group consisting of: or a pharmaceutically acceptable salt of any of the foregoing.
  • the R°, R 1 and R 2 are not all simultaneously -H.
  • R° is -H and the ring to which it is attached, is substituted with a single substituent (other than -H) at one of R 1 or R 2 .
  • R° is -H, and R 1 and R 2 are not -H.
  • R 1 is -H and the ring to which it is attached is substituted with a single substituent (other than -H) at one of R° or R 2 .
  • R 1 is -H, and R° and R 2 are not -H.
  • R 2 is -H and the ring to which it is attached is substituted with a single substituent (other than -H) at one of R° or R 1 .
  • R 2 is -H, and R° and R 1 are not -H. In other embodiments, R°, R 1 and R 2 are not -H.
  • an SHMT inhibitor is a compound of Formula (V): or a pharmaceutically acceptable salt thereof, wherein:
  • Z is N or CR 4 ;
  • X is O, S, CH 2 , or NR 6 ;
  • R°, R 1 and R 2 are each independently selected from -H, halogen, hydroxyl, nitro, nitrile, - SOR 11 , -S(0) 2 R u , -S(0) 2 NR 10 R 12 , -OR 11 , -0C(0)R 12 , -C(0)0R 12 , -C(0)R n , -C(O)NR 10 R 12 , - NR'°R 12 , -N(R 12 )C(0)R u , -NS(0) 2 R 12 , substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstitute
  • R 3 is selected from-H, halogen, hydroxyl, nitro, nitrile, -SOR 11 , -S(0) 2 R u , - S(O) 2 NR 10 R 12 , -OR 11 , -0C(0)R 12 , -C(0)0R 12 , -C(0)R u , -C(O)NR 10 R 12 , -NR 10 R 12 , - N(R 12 )C(0)R u , -NS(0) 2 R 12 , substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted Ci-C 6 haloal
  • R 4 is selected from -H, -NR 10 R 12 , -C(O)NR 10 R 12 , -N(R 12 )C(0)R u , nitrile, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted heteroarylalkyl;
  • R 5 is selected from -H, -NR 10 R 12 , -C(O)NR 10 R 12 , -N(R 12 )C(0)R u , nitrile, substituted or unsubstituted C C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted heteroarylalkyl, or R 5 and R 4 taken together with the respective carbon atom to which they are attached form a substituted or unsubstituted 4-12 membered ring;
  • R 6 is selected from H, substituted or unsubstituted C C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted heteroarylalkyl;
  • R 7 and R 8 are each independently selected from -H, -NR 10 R 12 , -C(O)NR 10 R 12 , - N(R 12 )C(0)R u , nitrile, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted heteroarylalkyl; each occurrence of R 11 is independently selected from substituted or unsubstituted C r C alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and each occurrence of R 10 and R 12 is each independently selected from -H, substituted or unsub
  • the compounds of Formula (V) are represented by Formula (Va) (wherein the R groups are as described above for Formula (V)):
  • Formula (Va) or a pharmaceutically acceptable salt thereof.
  • the compounds of Formula (V) are represented Formula (Vb) (wherein the R groups are as described above for Formula (V)):
  • R°, R 1 and R 2 are each independently selected from -H, halogen, hydroxyl, nitro, nitrile, -SOR 11 , -S(0) 2 R u , - S(O) 2 NR 10 R 12 , -OR 11 , -C(0)0R 12 , -C(0)R u , -C(O)NR 10 R 12 , -NR 10 R 12 , -N(R 12 )C(0)R u , - NS(0) 2 R 12 , substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroarylalkyl,
  • R° is selected from hydroxyl, -S(0) 2 R u , -S(O) 2 NR 10 R 12 , -OR 11 , -C(O)NR 10 R 12 , -NR 10 R 12 , -N(R 12 )C(0)R u , or -
  • R° is selected from -H, halogen, substituted or unsubstituted Ci-C 6 haloalkyl, substituted or unsubstituted Ci-C 6 haloalkoxy, or substituted or unsubstituted Ci-C 6 alkyl. In other embodiments R° is -H.
  • R 1 and R 2 are each independently selected from -H, halogen, hydroxyl, nitro, nitrile, -OR 11 , substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted Ci-C 6 haloalkyl, substituted or unsubstituted Ci-C 6 haloalkoxy.
  • R° is selected from -H, halogen, substituted or unsubstituted Ci-C 6 haloalkyl, substituted or unsubstituted Ci-C 6 haloalkoxy, or substituted or unsubstituted Ci-C 6 alkyl.
  • R° is -H.
  • R 1 and R 2 are each independently selected from -H, methoxy, fluoro, chloro, bromo, hydroxyl, nitro, nitrile, methyl, trifluoromethyl, or trifluorom ethoxy.
  • R° is selected from -H, halogen, substituted or unsubstituted Ci-C 6 haloalkyl, substituted or unsubstituted C r C haloalkoxy, or substituted or unsubstituted Ci-C 6 alkyl.
  • R° is -H.
  • R 1 and R 2 are each trifluoromethyl.
  • R° is selected from -H, halogen, substituted or unsubstituted C C 6 haloalkyl, substituted or unsubstituted Ci-C 6 haloalkoxy, or substituted or unsubstituted Ci-C 6 alkyl.
  • R° is -H.
  • R 3 is selected from-H, halogen, hydroxyl, nitro, nitrile, substituted or unsubstituted C C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 3 is selected substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 3 is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl. In certain embodiments, any of the foregoing may be optionally substituted.
  • R 3 is isopropyl or cyclopropyl. In certain embodiments, any of the foregoing may be optionally substituted.
  • R 4 and R 5 are each independently selected from -H, substituted or unsubstituted C C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted arylalkyl.
  • R 4 and R 5 are each independently selected from -H, substituted or unsubstituted C C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted arylalkyl.
  • R 4 and R 5 are each independently selected from -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or benzyl. In certain embodiments, any of the foregoing, except -H, may be optionally substituted.
  • R 4 and R 5 are independently -H or methyl. In certain embodiments, methyl may be optionally substituted.
  • R 5 and R 4 taken together with the respective carbon atom to which they are attached form a 4-12 membered ring selected from substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 5 and R 4 taken together with the respective carbon atom to which they are attached form a substituted or unsubstituted 4-12 membered ring containing 0-4 heteroatoms (0, 1, 2, 3 or 4) independently selected from N, O, or S.
  • the 4-12 membered ring is a monocyclic ring. In certain embodiments of any of the foregoing or following, the 4-12 membered ring is a polycyclic ring. In certain embodiments of any of the foregoing or following, the 4-12 membered ring is a bicyclic ring. In certain embodiments of any of the foregoing or following, when the 4-12 membered ring is a polycyclic ring, each ring is independently selected from saturated or unsaturated, and each ring may independently contain one or more heteroatoms (e.g., for a total of 1, 2, 3, 4 or 4 heteroatoms).
  • R 5 and R 4 taken together with the respective carbon atom to which they are attached form a phenyl ring.
  • the phenyl ring may be optionally substituted.
  • R 6 is selected from H, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted arylalkyl.
  • R 6 is selected from -H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, or benzyl. In certain embodiments, any of the foregoing may be optionally substituted.
  • R 6 is -H.
  • R 7 and R 8 are each independently selected from -H, -NR 10 R 12 , -C(O)NR 10 R 12 , -N(R 12 )C(0)R u , nitrile, methyl, ethyl, isopropyl, cyclopropryl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or benzyl.
  • R 7 is selected from -H, - NH 2 , methyl, or phenyl. In certain embodiments, any of the foregoing except -H, may be optionally substituted.
  • R 8 is selected from -H, nitrile, or -C(0)NH 2 .
  • -C(0)NH 2 may be optionally substituted.
  • each occurrence of R 11 is independently selected from substituted or unsubstituted Ci-C 6 alkyl or substituted or unsubstituted cycloalkyl. In certain embodiments, there is no occurrence of R 11 .
  • each occurrence of R 10 and R 12 is each independently selected from -H, substituted or unsubstituted Ci-C 6 alkyl, or substituted or unsubstituted cycloalkyl, such as from -H, or substituted or unsubstituted Ci-C 6 alkyl.
  • each occurrence of R 10 and R 12 is -H. In certain embodiments, there is no occurrence of R 10 and/or R 12 .
  • the disclosure provides a pharmaceutically acceptable salt thereof or an enantiomer thereof.
  • the R°, R 1 and R 2 are not all simultaneously -H.
  • R° is -H and the ring to which it is attached, is substituted with a single substituent (other than -H) at one of R 1 or R 2 .
  • R° is -H, and R 1 and R 2 are not -H.
  • R 1 is -H and the ring to which it is attached is substituted with a single substituent (other than -H) at one of R° or R 2 .
  • R 1 is -H, and R° and R 2 are not -H.
  • R 2 is -H and the ring to which it is attached is substituted with a single substituent (other than -H) at one of R° or R 1 .
  • R 2 is -H, and R° and R 1 are not -H. In other embodiments, R°, R 1 and R 2 are not -H.
  • R 7 when Z is N, and R 8 is H, R 7 cannot be substituted or unsubstituted aryl.
  • R 8 when R 4 and R 5 taken together with the respective carbon atoms to which they are attached for a substituted aryl ring, R 8 is not -H, -OH, or -CN.
  • the compound of Formulae (V), (Va), or (Vb) is: or a pharmaceutically acceptable salt thereof.
  • an SHMT inhibitor is a compound represented by Formula (VI):
  • R°, R 1 and R 2 are each independently selected from -H, halogen, hydroxyl, nitro, nitrile, - SOR 11 , -S(0) 2 R u , -S(0) 2 NR 10 R 12 , -OR 11 , -OC(0)R 12 , -C(0)OR 12 , -C(0)R n , -C(O)NR 10 R 12 , - NR 10 R 12 , -N(R 12 )C(0)R u , -NS(0) 2 R 12 , substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted Ci-
  • R 3 is selected from-H, halogen, hydroxyl, nitro, nitrile, -SOR 11 , -S(0) 2 R u , - S(O) 2 NR 10 R 12 , -OR 11 , -OC(0)R 12 , -C(0)OR 12 , -C(0)R u , -C(O)NR 10 R 12 , -NR 10 R 12 , - N(R 12 )C(0)R u , -NS(0) 2 R 12 , substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted Ci-C 6 haloalkyl
  • R 6 is selected from -H, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl substituted or unsubstituted arylalkyl, or substituted or unsubstituted heteroarylalkyl;
  • R 7 and R 8 are each independently selected from -H, -NR 10 R 12 , -C(O)NR 10 R 12 , - N(R 12 )C(0)R u , nitrile, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted heteroarylalkyl; each occurrence of R 11 is independently selected from substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and each occurrence of R 10 and R 12 is each independently selected from -H, substituted or unsub
  • the compounds of Formula (VI) are represented by Formula (Via) (wherein the R groups are as described above for Formula (VI)):
  • the compounds of Formula (VI) are represented by Formula (VIb) (wherein the R groups are as described above for Formula (VI)):
  • R°, R 1 and R 2 are each independently selected from -H, halogen, hydroxyl, nitro, nitrile, -S(0) 2 R u , -S(O) 2 NR 10 R 12 , - OR 11 , -C(O)NR 10 R 12 , -NR 10 R 12 , -N(R 12 )C(0)R u , or -NS(0) 2 R 12 , substituted or unsubstituted C C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Ci-C 6 haloalkyl, or substituted or unsubstituted Ci-C 6 haloalkoxy.
  • R° is selected from hydroxyl, -S(0) 2 R u , -S(O) 2 NR 10 R 12 , -OR 11 , -C(O)NR 10 R 12 , -NR 10 R 12 , -N(R 12 )C(0)R u , or - NS(0) 2 R 12 .
  • R° is selected from -H, halogen, substituted or unsubstituted Ci-C 6 haloalkyl, substituted or unsubstituted Ci-C 6 haloalkoxy, or substituted or unsubstituted Ci-C 6 alkyl.
  • R° is -H.
  • R 1 and R 2 are each independently selected from -H, halogen, hydroxyl, nitro, nitrile, -OR 11 , substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted Ci-C 6 haloalkyl, or substituted or unsubstituted Ci-C 6 haloalkoxy.
  • R° is selected from -H, halogen, substituted or unsubstituted Ci-C 6 haloalkyl, substituted or unsubstituted Ci-C 6 haloalkoxy, or substituted or unsubstituted Ci-C 6 alkyl.
  • R° is -H.
  • R 1 and R 2 are each independently selected from -H, methoxy, fluoro, chloro, bromo, hydroxyl, nitro, nitrile, methyl, trifluoromethyl, or trifluorom ethoxy.
  • R° is selected from -H, halogen, substituted or unsubstituted Ci-C 6 haloalkyl, substituted or unsubstituted Ci-C 6 haloalkoxy, or substituted or unsubstituted Ci-C 6 alkyl.
  • R° is -H.
  • R 1 and R 2 are each trifluoromethyl.
  • R° is selected from -H, halogen, substituted or unsubstituted Ci-C 6 haloalkyl, substituted or unsubstituted Ci-C 6 haloalkoxy, or substituted or unsubstituted Ci-C 6 alkyl.
  • R° is -H.
  • R 3 is selected from-H, halogen, hydroxyl, nitro, nitrile, substituted or unsubstituted C r C alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 3 is selected substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 3 is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl. In certain embodiments, any of the foregoing may be optionally substituted.
  • R 3 is isopropyl or cyclopropyl. In certain embodiments, any of the foregoing may be optionally substituted.
  • R 5 is selected from -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or benzyl. In certain embodiments, any of the foregoing except -H, may be optionally substituted.
  • R 5 is -H.
  • R 6 is selected from H, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted arylalkyl.
  • R 6 is selected from -H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl or benzyl. In certain embodiments, any of the foregoing except -H, may be optionally substituted. [00312] In certain embodiments of any of the foregoing or following, R 6 is -H.
  • R 7 and R 8 are each independently selected from -H, -NR 10 R 12 , -C(O)NR 10 R 12 , -N(R 12 )C(0)R u , nitrile, methyl, ethyl, isopropyl, cyclopropryl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or benzyl.
  • R 7 is selected from - NH 2 , methyl, or phenyl. In certain embodiments, any of the foregoing, may be optionally substituted.
  • R 8 is selected from -H, nitrile, or -C(0)NH 2 .
  • -C(0)NH 2 may be optionally substituted.
  • each occurrence of R 11 is independently selected from substituted or unsubstituted C C 6 alkyl or substituted or unsubstituted cycloalkyl. In certain embodiments, there is no occurrence of R 11 .
  • each occurrence of R 10 and R 12 is each independently selected from -H, substituted or unsubstituted Ci-C 6 alkyl, or substituted or unsubstituted cycloalkyl, such as from -H, or substituted or unsubstituted Ci-C 6 alkyl.
  • each occurrence of R 10 and R 12 is -H. In certain embodiments, there is no occurrence of R 10 and/or R 12 .
  • R° is selected from -H, halogen, hydroxyl, nitro, nitrile, -S(0) 2 R u , -S(O) 2 NR 10 R 12 , -OR 11 , -C(O)NR 10 R 12 , -NR 10 R 12 , - N(R 12 )C(0)R u , or -NS(0) 2 R 12 , substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted Ci-C 6 haloalkyl, or substituted or unsubstituted Ci-C 6 haloalkoxy;
  • R 1 and R 2 are each independently selected from -H, methoxy, fluoro, chloro, bromo, hydroxyl, nitro, nitrile, methyl, or trifluoromethyl;
  • R 3 is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl;
  • R 5 is selected from -H, methyl, ethyl, propyl or isopropyl
  • R 6 is selected from -H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or benzyl;
  • R 7 and R 8 are each independently selected from -H, -NH 2 , -C(0)NH 2 , nitrile, methyl, ethyl, isopropyl, cyclopropryl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or benzyl.
  • R° is selected from -H, hydroxyl, -S(0) 2 R u , -S(O) 2 NR 10 R 12 , -OR 11 , -C(O)NR 10 R 12 , -NR 10 R 12 , -N(R 12 )C(0)R u , or - NS(0) 2 R 12 ;
  • R 1 and R 2 are each trifluoromethyl
  • R 3 is isopropyl or cyclopropyl
  • R 5 is -H;
  • R 6 is -H;
  • R 7 is selected from -NH 2 , methyl, or phenyl; and R 8 is selected from H, nitrile, or -C(0)NH 2.
  • the compound is selected from: or a pharmaceutically acceptable salt of any of the foregoing.
  • the R°, R 1 and R 2 are not all simultaneously -H.
  • R° is -H and the ring to which it is attached, is substituted with a single substituent (other than -H) at one of R 1 or R 2 .
  • R° is -H, and R 1 and R 2 are not -H.
  • R 1 is -H and the ring to which it is attached is substituted with a single substituent (other than -H) at one of R° or R 2 .
  • R 1 is -H, and R° and R 2 are not -H.
  • R 2 is -H and the ring to which it is attached is substituted with a single substituent (other than -H) at one of R° or R 1 .
  • R 2 is -H, and R° and R 1 are not -H. In other embodiments, R°, R 1 and R 2 are not -H.
  • R 7 is not a substituted or unsubstituted aryl.
  • an SHMT inhibitor is a compound of Formula (VII):
  • R°, R 1 and R 2 are each independently selected from -H, halogen, hydroxyl, nitro, nitrile, - SOR 11 , -S(0) 2 R u , -S(0) 2 NR 10 R 12 , -OR 11 , -0C(0)R 12 , -C(0)0R 12 , -C(0)R n , -C(O)NR 10 R 12 , - NR 10 R 12 , -N(R 12 )C(0)R u , -NS(0) 2 R 12 , substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted
  • R 3 is selected from-H, halogen, hydroxyl, nitro, nitrile, -SOR 11 , -S(0) 2 R u , - S(O) 2 NR 10 R 12 , -OR 11 , -0C(0)R 12 , -C(0)0R 12 , -C(0)R u , -C(O)NR 10 R 12 , -NR 10 R 12 , - N(R 12 )C(0)R u , -NS(0) 2 R 12 , substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted Ci-C 6 haloal
  • R 4 and R 5 are independently selected from H, -NR 10 R 12 , -C(O)NR 10 R 12 , -N(R 12 )C(0)R u , nitrile, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted heteroarylalkyl, or R 5 and R 4 taken together with the respective carbon atom to which they are attached form a substituted or unsubstituted 4-12 membered ring;
  • R 6 is selected from -H, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted heteroarylalkyl;
  • R 7 and R 8 are each independently selected from -H, -NR 10 R 12 , -C(O)NR 10 R 12 , - N(R 12 )C(0)R u , nitrile, substituted or unsubstituted C r C alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted heteroarylalkyl; each occurrence of R 11 is independently selected from substituted or unsubstituted C C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and each occurrence of R 10 and R 12 is each independently selected from -H, substituted or unsubsti
  • R°, R 1 and R 2 are each independently selected from -H, halogen, hydroxyl, nitro, nitrile, -SOR 11 , -S(0) 2 R u , - S(O) 2 NR 10 R 12 , -OR 11 , -C(0)0R 12 , -C(0)R u , -C(O)NR 10 R 12 , -NR 10 R 12 , -N(R 12 )C(0)R u , - NS(0) 2 R 12 , substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroarylalkyl,
  • R° is selected from hydroxyl, -S(0) 2 R u , -S(O) 2 NR 10 R 12 , -OR 11 , -C(O)NR 10 R 12 , -NR 10 R 12 , -N(R 12 )C(0)R u , or - NS(0) 2 R 12 .
  • R° is selected from -H, halogen, substituted or unsubstituted Ci-C 6 haloalkyl, substituted or unsubstituted Ci-C 6 haloalkoxy, or substituted or unsubstituted Ci-C 6 alkyl.
  • R° is -H.
  • R 1 and R 2 are each independently selected from -H, hydroxyl, -S(0) 2 R u , -S(O) 2 NR 10 R 12 , -OR 11 , -C(O)NR 10 R 12 , - NR 10 R 12 , -N(R 12 )C(0)R u , or -NS(0) 2 R 12 .
  • R 1 and R 2 are each independently selected from -H, methoxy, fluoro, chloro, bromo, hydroxyl, nitro, nitrile, methyl, trifluoromethyl, or trifluorom ethoxy.
  • R° is selected from -H, halogen, substituted or unsubstituted Ci-C 6 haloalkyl, substituted or unsubstituted Ci-C 6 haloalkoxy, or substituted or unsubstituted Ci-C 6 alkyl.
  • R° is -H.
  • R 1 and R 2 are each trifluorom ethyl.
  • R° is selected from -H, halogen, substituted or unsubstituted C C 6 haloalkyl, substituted or unsubstituted Ci-C 6 haloalkoxy, or substituted or unsubstituted C C 6 alkyl.
  • R° is -H.
  • R 3 is selected from-H, halogen, hydroxyl, nitro, nitrile, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 3 is selected substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 3 is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl. In certain embodiments, any of the foregoing, may be optionally substituted.
  • R 3 is isopropyl. In certain embodiments, isopropyl may be optionally substituted.
  • R 4 and R 5 are independently selected from H, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted heteroarylalkyl.
  • R 4 and R 5 are each independently selected from -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or benzyl. In certain embodiments, any of the foregoing except - H, may be optionally substituted.
  • R 4 and R 5 are each independently -H or methyl. In certain embodiments, methyl may be optionally substituted.
  • R 5 and R 4 taken together with the respective carbon atoms to which they are attached form a substituted or unsubstituted 4-12 membered ring.
  • R 5 and R 4 taken together with the respective carbon atom to which they are attached form a 4-12 membered ring selected from substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
  • R 5 and R 4 taken together with the respective carbon atom to which they are attached form a substituted or unsubstituted 4-12 membered ring containing 0-4 heteroatoms (0, 1, 2, 3 or 4) independently selected from N, O, or S.
  • the 4-12 membered ring is a monocyclic ring. In certain embodiments of any of the foregoing or following, the 4-12 membered ring is a polycyclic ring. In certain embodiments of any of the foregoing or following, the 4-12 membered ring is a bicyclic ring. In certain embodiments of any of the foregoing or following, when the 4-12 membered ring is a polycyclic ring, each ring is independently selected from saturated or unsaturated, and each ring may independently contain one or more heteroatoms.
  • R 5 and R 4 taken together with the respective carbon atom to which they are attached form a phenyl ring.
  • the phenyl ring may be optionally substituted.
  • R 6 is selected from H, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted arylalkyl.
  • R 6 is selected from -H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, or benzyl. In certain embodiments, any of the foregoing except -H, may be optionally substituted. [00345] In certain embodiments of any of the foregoing or following, R 6 is -H.
  • R 7 and R 8 are each independently selected from-H, -NR 10 R 12 , -C(O)NR 10 R 12 , -N(R 12 )C(0)R u , nitrile, methyl, ethyl, isopropyl, cyclopropryl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or benzyl.
  • R 7 is selected from -H, - NH 2 , methyl, or phenyl. In certain embodiments, any of the foregoing except -H, may be optionally substituted.
  • R 8 is selected from -H, nitrile, or -C(0)NH 2. In certain embodiments, -C(0)NH 2 may be optionally substituted.
  • each occurrence of R 11 is independently selected from substituted or unsubstituted C C 6 alkyl or substituted or unsubstituted cycloalkyl. In certain embodiments, there is no occurrence of R 11 .
  • each occurrence of R 10 and R 12 is each independently selected from -H, substituted or unsubstituted C C 6 alkyl, or substituted or unsubstituted cycloalkyl, such as from -H, or substituted or unsubstituted Ci-C 6 alkyl.
  • each occurrence of R 10 and R 12 is -H. In certain embodiments, there is no occurrence of R 10 and/or R 12 .
  • the compound is selected from: or a pharmaceutically acceptable salt of any of the foregoing.
  • the compound of Formula (VII), (Vila), or (Vllb) is: or a pharmaceutically acceptable salt of either of the foregoing.
  • the R°, R 1 and R 2 are not all simultaneously -H.
  • R° is -H and the ring to which it is attached, is substituted with a single substituent (other than -H) at one of R 1 or R 2 .
  • R° is -H, and R 1 and R 2 are not -H.
  • R 1 is -H and the ring to which it is attached is substituted with a single substituent (other than -H) at one of R° or R 2 .
  • R 1 is -H, and R° and R 2 are not -H.
  • R 2 is -H and the ring to which it is attached is substituted with a single substituent (other than -H) at one of R° or R 1 .
  • R 2 is -H, and R° and R 1 are not -H. In other embodiments, R°, R 1 and R 2 are not -H.
  • A, D, G and K are each independently N or CR 15 , provided that no more than two of A,
  • R°, R 1 and R 2 are each independently selected from -H, halogen, hydroxyl, nitro, -SOR 11 , -S(0) 2 R u , -S(0) 2 NR 10 R 12 , -OR 11 , -0C(0)R 12 , -C(0)0R 12 , -C(0)R u , -C(O)NR 10 R 12 , -NR 10 R 12 , - N(R 12 )C(0)R u , -NS(0) 2 R 12 substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted Ci-C 6 haloalky
  • R 3 is selected from -H, halogen, hydroxyl, nitro, nitrile, -SOR 11 , -S(0) 2 R u , - S(O) 2 NR 10 R 12 , -OR 11 , -0C(0)R 12 , -C(0)0R 12 , -C(0)R u , -C(O)NR 10 R 12 , -NR 10 R 12 , - N(R 12 )C(0)R u , -NS(0) 2 R 12 , substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted Ci-C 6 halo
  • R 7 and R 8 are each independently selected from -H, -NR 10 R 12 , -C(O)NR 10 R 12 , - N(R 12 )C(0)R u , nitrile, substituted or unsubstituted C r C alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted heteroarylalkyl; each occurrence of R 11 is independently selected from substituted or unsubstituted C r C alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each occurrence of R 10 and R 12 is each independently selected from -H, substituted or unsubsti
  • the compounds of Formula (VIII) are represented by Formula (Villa) (wherein the R groups are as described above for Formula (VIII)):
  • the compounds of Formula (VIII) are represented by Formula (Vlllb) (wherein the R groups are as described above for Formula (VIII)):
  • R°, R 1 , and R 2 are each independently selected from -H, halogen, hydroxyl, nitro, nitrile, -SOR 11 , -S(0) 2 R u , - S(O) 2 NR 10 R 12 , -OR 11 , -C(0)0R 12 , -C(0)R u , -C(O)NR 10 R 12 , -NR 10 R 12 , -N(R 12 )C(0)R u , - NS(0) 2 R 12 , substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted hetero
  • R° is selected from -H, hydroxyl, -S(0) 2 R u , -S(O) 2 NR 10 R 12 , -OR 11 , -C(O)NR 10 R 12 , -NR 10 R 12 , -N(R 12 )C(0)R u , or - NS(0) 2 R 12 .
  • R° is selected from -H, halogen, substituted or unsubstituted Ci-C 6 haloalkyl, substituted or unsubstituted Ci-C 6 haloalkoxy, or substituted or unsubstituted Ci-C 6 alkyl.
  • R° is -H.
  • R 1 and R 2 are each independently selected from -H, halogen, hydroxyl, nitro, nitrile, -ORn, substituted or unsubstituted Ci-C 6 alkyl, or substituted or unsubstituted Ci-C 6 haloalkyl, substituted or unsubstituted C C 6 haloalkoxy.
  • R° is selected from -H, halogen, substituted or unsubstituted Ci-C 6 haloalkyl, substituted or unsubstituted C r C haloalkoxy, or substituted or unsubstituted Ci-C 6 alkyl.
  • R° is -H.
  • R 1 and R 2 are each independently selected from -H, methoxy, fluoro, chloro, bromo, hydroxyl, nitro, nitrile, methyl, or trifluoromethyl, or trifluorom ethoxy.
  • R° is selected from -H, halogen, substituted or unsubstituted Ci-C 6 haloalkyl, substituted or unsubstituted Ci-C 6 haloalkoxy, or substituted or unsubstituted Ci-C 6 alkyl.
  • R° is -H.
  • R 1 and R 2 are each trifluorom ethyl.
  • R° is selected from -H, halogen, substituted or unsubstituted Ci-C 6 haloalkyl, substituted or unsubstituted Ci-C 6 haloalkoxy, or substituted or unsubstituted Ci-C 6 alkyl.
  • R° is -H.
  • R 3 is selected from-H, halogen, hydroxyl, nitro, nitrile, substituted or unsubstituted C r C alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 3 is selected substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 3 is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl. In certain embodiments, any of the foregoing, may be optionally substituted.
  • R 3 is isopropyl. In certain embodiments, isopropyl may be optionally substituted.
  • R 7 and R 8 are each independently selected from -H, -NR 10 R 12 , -C(O)NR 10 R 12 , -N(R 12 )C(0)R u , nitrile, methyl, ethyl, isopropyl, cyclopropryl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or benzyl.
  • any of the foregoing except -H may be optionally substituted.
  • R 7 is methyl or phenyl. In certain embodiments, any of the foregoing may be optionally substituted.
  • R 8 is nitrile or - C(0)NH 2.
  • -C(0)NH 2 may be optionally substituted.
  • each occurrence of R 11 is independently selected from substituted or unsubstituted C r C alkyl or substituted or unsubstituted cycloalkyl. In certain embodiments, there is no occurrence of R 11 .
  • each occurrence of R 10 and R 12 is each independently selected from -H, substituted or unsubstituted Ci-C 6 alkyl, or substituted or unsubstituted cycloalkyl, such as from -H, or substituted or unsubstituted Ci-C 6 alkyl. In certain embodiments, each occurrence of R 10 and R 12 is -H. In certain embodiments, there is no occurrence of R 10 and/or R 12 .
  • R° is independently selected from -H, halogen, hydroxyl, nitro, nitrile, -SOR 11 , -S(0) 2 R u , -S(O) 2 NR 10 R 12 , -OR 11 , - OC(0)R 12 , -C(0)OR 12 , -C(0)R u , -C(O)NR 10 R 12 , -NR 10 R 12 , -N(R 12 )C(0)R u , -NS(0) 2 R 12 , substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroarylalkyl, substitute
  • R 3 is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl;
  • R 7 and R 8 are each independently selected from H, -NH 2 , -C(0)NH 2 , nitrile, methyl, ethyl, isopropyl, cyclopropryl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or benzyl; and
  • A, D, G and K is each independently selected from N or CR 15 , wherein each occurrence of R 15 is independently selected from -H, halogen, hydroxyl, nitro, nitrile, substituted or unsubstituted C C 6 alkoxy, substituted or unsubstituted Ci-C 6 alkyl, or substituted or unsubstituted Ci-C 6 haloalkyl, substituted or unsubstituted Ci-C 6 haloalkoxy.
  • R° is selected from -H, hydroxyl, -S(0) 2 R u , -S(O) 2 NR 10 R 12 , -OR 11 , -C(O)NR 10 R 12 , -NR 10 R 12 , -N(R 12 )C(0)R u , or - NS(0) 2 R 12 ;
  • R 1 and R 2 are each trifluoromethyl
  • R 3 is isopropyl
  • R 7 is -NH 2 methyl or phenyl
  • R 8 is nitrile or -C(0)NH 2 ;
  • A, D, G and K is each independently selected from N or CR 15 , wherein each occurrence of R 15 is independently selected from -H, halogen, hydroxyl, nitro, nitrile, substituted or unsubstituted Ci-C 6 alkoxy, substituted or unsubstituted Ci-C 6 alkyl, or substituted or unsubstituted Ci-C 6 haloalkyl, substituted or unsubstituted Ci-C 6 haloalkoxy.
  • the compound is selected from: or a pharmaceutically acceptable salt thereof.
  • the R°, R 1 and R 2 are not all simultaneously -H.
  • R° is -H and the ring to which it is attached, is substituted with a single substituent (other than -H) at one of R 1 or R 2 .
  • R° is -H, and R 1 and R 2 are not -H.
  • R 1 is -H and the ring to which it is attached is substituted with a single substituent (other than -H) at one of R° or R 2 .
  • R 1 is -H, and R° and R 2 are not -H.
  • R 2 is -H and the ring to which it is attached is substituted with a single substituent (other than -H) at one of R° or R 1 .
  • R 2 is -H, and R° and R 1 are not -H. In other embodiments, R°, R 1 and R 2 are not -H.
  • an SHMT inhibitor is a compound represented by Formula (IX):
  • R°, R 1 and R 2 are each independently selected from -H, halogen, hydroxyl, nitro, nitrile, -
  • R 3 is selected from-H, halogen, hydroxyl, nitro, nitrile, -SOR 11 , -S(0) 2 R u , - S(O) 2 NR 10 R 12 , -OR 11 , -0C(0)R 12 , -C(0)0R 12 , -C(0)R u , -C(O)NR 10 R 12 , -NR 10 R 12 , - N(R 12 )C(0)R u , -NS(0) 2 R 12 , substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted Ci-C 6 haloal
  • R 4 is selected from H, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted heteroarylalkyl;
  • R 5 , R 6 and R 7 are each independently selected from -H, -C(0)R u , substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted heteroarylalkyl, or R 5 is selected from any of the foregoing and R 6 and R 7 taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted 3- 6 membered ring; each occurrence of R 11 is independently selected from substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and
  • the compound of Formula (IX) is represented by Formula (IXa) (wherein the R groups are as described above for Formula (IX)):
  • the compound of Formu81a (IX) is represented by Formula (IXb) (wherein the R groups are as described above for Formula (IX)):
  • R°, R 1 and R 2 are each independently selected from -H, halogen, hydroxyl, nitro, nitrile, -SOR 11 , -S(0) 2 R u , - S(O) 2 NR 10 R 12 , -OR 11 , -C(0)OR 12 , -C(0)R u , -C(O)NR 10 R 12 , -NR 10 R 12 , -N(R 12 )C(0)R u , - NS(0) 2 R 12 , substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroarylalkyl, substitute
  • R° is selected from hydroxyl, -S(0) 2 R u , -S(O) 2 NR 10 R 12 , -OR 11 , -C(O)NR 10 R 12 , -NR 10 R 12 , -N(R 12 )C(0)R u , or -
  • R° is selected from -H, halogen, substituted or unsubstituted Ci-C 6 haloalkyl, substituted or unsubstituted Ci-C 6 haloalkoxy, or substituted or unsubstituted Ci-C 6 alkyl. In other embodiments R° is -H.
  • R 1 and R 2 are each independently selected from -H, halogen, hydroxyl, nitro, nitrile, -OR 11 , substituted or unsubstituted Ci-C 6 alkyl, or substituted or unsubstituted Ci-C 6 haloalkyl, substituted or unsubstituted Ci-C 6 haloalkoxy.
  • R° is selected from -H, halogen, substituted or unsubstituted Ci-C 6 haloalkyl, substituted or unsubstituted Ci-C 6 haloalkoxy, or substituted or unsubstituted Ci-C 6 alkyl.
  • R° is -H.
  • R 1 and R 2 are each independently selected from -H, methoxy, fluoro, chloro, bromo, hydroxyl, nitro, nitrile, methyl, trifluoromethyl, or trifluorom ethoxy.
  • R° is selected from -H, halogen, substituted or unsubstituted Ci-C 6 haloalkyl, substituted or unsubstituted C r C haloalkoxy, or substituted or unsubstituted Ci-C 6 alkyl.
  • R° is -H.
  • R 1 and R 2 are each independently selected from H, methoxy, chloro, nitro, nitrile, or trifluoromethyl.
  • R° is selected from -H, halogen, substituted or unsubstituted Ci-C 6 haloalkyl, substituted or unsubstituted Ci-C 6 haloalkoxy, or substituted or unsubstituted Ci-C 6 alkyl.
  • R° is -H.
  • R1 and R 2 are each trifluoromethyl.
  • R° is selected from -H, halogen, substituted or unsubstituted Ci-C 6 haloalkyl, substituted or unsubstituted Ci-C 6 haloalkoxy, or substituted or unsubstituted Ci-C 6 alkyl.
  • R° is -H.
  • R 3 is selected from-H, halogen, hydroxyl, nitro, nitrile, substituted or unsubstituted C r C alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 3 is selected substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 3 is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl. In certain embodiments, any of the foregoing may be optionally substituted.
  • R 3 is selected from isopropyl, cyclopropyl, or cyclobutyl. In certain embodiments, any of the foregoing may be optionally substituted.
  • R 3 is cyclobutyl. In certain embodiments, cyclobutyl may be optionally substituted.
  • R 4 is selected from -H, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted arylalkyl.
  • R 4 is selected from -H, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted arylalkyl.
  • R 4 is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or benzyl. In certain embodiments, any of the foregoing may be optionally substituted.
  • R 4 is methyl or isopropyl. In certain embodiments, any of the foregoing may be optionally substituted.
  • R 4 is methyl. In certain embodiments, methyl may be optionally substituted.
  • R 5 , R 6 and R 7 are each independently selected from -H, -C(0)R u , substituted or unsubstituted C r C alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, or R 5 is selected from any of the foregoing and R 6 and R 7 taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted 3-6 membered ring.
  • R 5 , R 6 and R 7 are each independently selected from -H, -C(0)R u , substituted or unsubstituted C r C alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted arylalkyl.
  • R 5 , R 6 and R 7 are each independently selected from -H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, or COCH 3.
  • any of the foregoing, except -H, may be optionally substituted.
  • R 5 , R 6 and R 7 are each independently selected from H, methyl, phenyl, or -COCH 3. In certain embodiments, any of the foregoing, except -H, may be optionally substituted.
  • R 5 and R 6 are each independent selected from H, methyl or phenyl. In certain embodiments, any of the foregoing, except -H, may be optionally substituted.
  • R 7 is H.
  • the compound is selected from:
  • the R°, R 1 and R 2 are not all simultaneously -H.
  • R° is -H and the ring to which it is attached, is substituted with a single substituent (other than -H) at one of R 1 or R 2 .
  • R° is -H, and R 1 and R 2 are not -H.
  • R 1 is -H and the ring to which it is attached is substituted with a single substituent (other than -H) at one of R° or R 2 .
  • R 1 is -H, and R° and R 2 are not -H.
  • R 2 is -H and the ring to which it is attached is substituted with a single substituent (other than -H) at one of R° or R 1 .
  • R 2 is -H, and R° and R 1 are not -H.
  • R°, R 1 and R 2 are not -H.
  • the disclosure also provides variants of Formulae (IV), (V), (VI), (VII), (VIII), and
  • the SHMT inhibitor is selected from a compound in Table 2, or a pharmaceutically acceptable salt thereof.
  • an active agent described herein e.g ., an inhibitor of serine catabolism, such as an SHMT inhibitor
  • an active agent described herein is formulated with one or more pharmaceutically acceptable carriers, excipients and/or diluents.
  • the disclosure provides such compositions, including pharmaceutical compositions.
  • the compositions can be used in the methods described herein, e.g., to supply an agent described herein.
  • compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial g
  • Agents or pharmaceutical compositions may be administered to cells in vitro, such as by addition to culture media. Additionally or alternatively, agents or pharmaceutical compositions may be administered by a route of administration, such as oral, parenteral, intravenous, intra-arterial, cutaneous, subcutaneous, intramuscular, topical, intracranial, intraorbital, ophthalmic, intravitreal, intraventricular, intracap sular, intraspinal, intracisternal, intraperitoneal, intranasal, aerosol, central nervous system (CNS) administration, or administration by suppository. In some embodiments, an agent or pharmaceutical composition is administered topically, systemically, or locally.
  • a route of administration such as oral, parenteral, intravenous, intra-arterial, cutaneous, subcutaneous, intramuscular, topical, intracranial, intraorbital, ophthalmic, intravitreal, intraventricular, intracap sular, intraspinal, intracisternal, intraperitoneal, intranasal, aerosol,
  • agents and compositions may be formulated for administration by, for example, injection (e.g., intravenously, subcutaneously, or intramuscularly), inhalation or insufflation (either through the mouth or the nose) or oral, buccal, sublingual, transdermal, nasal, or parenteral administration.
  • Agents or compositions may also be formulated as part of an implant or device, or formulated for slow or extended release.
  • agents and compositions are preferably in a pyrogen-free, physiologically acceptable form.
  • a preferred pharmaceutical composition for intravenous, cutaneous, or subcutaneous injection should contain, in addition to the toxicity-reducing compounds, an isotonic vehicle such as Sodium Chloride Injection, Ringer’s Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, Lactated Ringer’s Injection, or other vehicle as known in the art.
  • an isotonic vehicle such as Sodium Chloride Injection, Ringer’s Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, Lactated Ringer’s Injection, or other vehicle as known in the art.
  • the pharmaceutical composition of the compound of the present disclosure may also contain stabilizers, preservatives, buffers, antioxidants, or other additives known to those of skill in the art. Techniques and formulations generally may be found in Remington’s Pharmaceutical Sciences, Meade Publishing Co., Easton, PA.
  • a composition may also contain adjuvants, such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin.
  • adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride
  • Agent(s) or compositions may be in the form of a tablet, capsule, powder, solution or elixir, for example, for oral administration.
  • the pharmaceutical composition may additionally contain a solid carrier such as a gelatin or an adjuvant.
  • the tablet, capsule, and powder may contain from about 5% to about 95% by weight of an active agent, and preferably from about 10% to about 90% by weight of the active agent.
  • a liquid carrier such as water, petroleum, oils of animal or plant origin such as peanut oil, mineral oils, phospholipids, tweens, triglycerides, including medium chain triglycerides, soybean oil, or sesame oil, or synthetic oils
  • the liquid form of the pharmaceutical composition may further contain physiological saline solution, dextrose or other saccharide solution, or glycols such as ethylene glycol, propylene glycol or polyethylene glycol.
  • the pharmaceutical composition typically contains from about 0.5% to about 90% by weight of an active agent, and preferably from about 1% to about 50% by weight of the active agent.
  • a composition may contain one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following:
  • fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid;
  • binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and/or acacia
  • humectants such as glycerol
  • disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate
  • solution retarding agents such as paraffin
  • absorption accelerators such as quaternary ammonium compounds
  • wetting agents such as, for example, cetyl alcohol and glycerol monostearate
  • absorbents such as kaolin and bentonite clay
  • lubricants such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof
  • coloring agents such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and/or aca
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol (ethanol), isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants such as wetting agents, e
  • the pharmaceutical compositions may be in the form of a liposome or micelles in which the toxicity -reducing compounds are combined, in addition to other pharmaceutically acceptable carriers, with amphipathic agents such as lipids which exist in aggregated form as micelles, insoluble monolayers, liquid crystals, or lamellar layers in aqueous solution.
  • Suitable lipids for liposomal formulation include, without limitation, monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids, saponin, bile acids, and the like. Preparation of such liposomal formulations is within the level of skill in the art, as disclosed, for example, in U.S.
  • Suspensions in addition to the active agent may contain suspending agents, such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • the amount of an active agent in a pharmaceutical composition will depend upon, for example, the nature and severity of the condition being treated, the agent used, and on the nature of prior treatments the patient has undergone. Ultimately, the practitioner will decide the amount of the active agent to use to treat each individual patient.
  • Representative doses of the present disclosure include, but are not limited to, about 0.001 mg to about 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to about 1000 mg, 0.001 mg to about 500 mg, 0.001 mg to about 250 mg, about 0.001 mg to 100 mg, about 0.001 mg to about 50 mg and about 0.001 mg to about 25 mg. It is contemplated that the various pharmaceutical compositions used to practice the methods of the present disclosure should contain, in some embodiments, about 0.1 pg to about 100 mg (preferably about 0.1 mg to about 50 mg, more preferably, about 1 mg to about 2 mg) of active agent per kg body weight.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as 2, 3, 4 or more sub-doses, per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations.
  • the daily dose can be divided, especially when relatively large amounts are administered as deemed appropriate, into several, for example, 2, 3 or 4 administrations. If appropriate, depending on individual behavior, it may be necessary to deviate upward or downward from the daily dose indicated.
  • compositions can include more than one active agent, e.g., a combination.
  • a combination comprising an inhibitor of serine catabolism (e.g, an SHMT inhibitor) and an additional therapeutic agent (e.g, an electron transport chain inhibitor).
  • an additional therapeutic agent e.g, an electron transport chain inhibitor.
  • a combination further includes a pharmaceutically acceptable carrier, excipient or diluent.
  • kits comprising an inhibitor of serine catabolism (e.g, an SHMT inhibitor), or a composition comprising the inhibitor of serine catabolism, and an additional therapeutic agent(s) (e.g, an electron transport chain inhibitor), or a composition comprising the additional therapeutic agent(s).
  • an inhibitor of serine catabolism e.g, an SHMT inhibitor
  • an additional therapeutic agent(s) e.g, an electron transport chain inhibitor
  • the kit further comprises written instructions for administering the inhibitor of serine catabolism and the additional therapeutic agent(s) to a subject to treat a disorder described herein.
  • NADH provides electrons for aerobic ATP production. In cells deprived of oxygen or with impaired electron transport chain activity, NADH accumulation can be toxic. To minimize such toxicity, elevated NADH inhibits the classical NADH producing pathways: glucose, glutamine, and fat oxidation.
  • glucose, glutamine, and fat oxidation are incorporated herein by reference.
  • folate-dependent serine catabolism also produces substantial NADH. Strikingly, when respiration is impaired, serine catabolism through methylene tetrahydrofolate dehydrogenase (MTHFD2) becomes a major NADH source.
  • MTHFD2 methylene tetrahydrofolate dehydrogenase
  • Mammals break down carbohydrates, amino acids, and fatty acids for energy generation (Chen et al., 2018; Hui et al., 2017; Kalucka et al., 2018; Lundsgaard et ah, 2018; Neinast et al., 2019).
  • TCA Through TCA turning in mitochondria, these nutrients are burned into C0 2 while producing reducing power in the form of NADH. Electrons from NADH are then transferred to mitochondrial complex I and downstream components of the electron transport chain (ETC), eventually reducing oxygen to water (Titov et al., 2016). By inducing a proton gradient, these reactions power mitochondrial ATP synthase, which provides the bulk of ATP in mammals.
  • the most common physiological impediment to respiration is hypoxia.
  • Respiration impairment can also be induced by genetic lesions of the ETC (e.g., in mitochondrial disorders) and by pharmaceuticals.
  • Metformin the first-line treatment for type 2 diabetes, acts at least in part as a complex I inhibitor (El-Mir et al., 2000; Fullerton et al., 2013; Hunter et al., 2018; Liu et al., 2016b; Madiraju et al., 2014; Madiraju et al., 2018; Owen et al., 2000; Wheaton et al., 2014).
  • the consequences of ETC inhibition may vary depending on the respiratory chain component involved. For example, the reduction of complexes III and IV is increased by hypoxia but not by complex I inhibition (Chandel et al., 1998; Wheaton et al., 2014).
  • NADH accumulation requires an alternative electron acceptor, such as pyruvate.
  • Major consequences of NADH accumulation include blockade of TCA turning, impairment de novo aspartate synthesis, and resulting decreases in protein and nucleotide synthesis (Birsoy et al., 2015; Gameiro et al., 2013; Mullen et al., 2012; Sullivan et al., 2015; Wise et al., 2011; Yoo et al., 2008).
  • MTHFD2 oxidizes 5,10- methylenetetrahydrofolate (THF) to generate the purine precursor 10-formyl-THF, while reducing NAD to NADH.
  • the mTORCl inhibitor rapamycin decreases MTHFD2 expression, normalizes 1C metabolism, and prolongs the survival of mice with engineered complex I deficiency (NDUSF4-/- mice) (Johnson et al., 2013; Khan et al., 2017; Zheng et al., 2016).
  • the functional importance of MTHFD2 in this context remains, however, unexplored. More generally, the reactions producing the accumulated NADH when ETC activity is impaired remain understudied.
  • mitochondrial serine catabolism can produce substantial NADH, especially in pancreas, spleen and tumors.
  • This pathway turns out to be the major source of NADH for cells with impaired ETC activity due to hypoxia, pharmacological ETC inhibition, or genetic ETC lesions.
  • inhibition of mitochondrial serine catabolism improved metabolic homeostasis and enhanced growth of cultured cells.
  • it slowed onset of spasticity in complex I deficient mice.
  • the studies described herein and in Yang et al. are based on setting up a tracing strategy to directly label active hydride in NADH by using deuterium labeled nutrients (serine, glutamine, lactate, fatty acids).
  • the present disclosure is based in part on the discovery that a significant fraction of mitochondrial NADH is derived from serine in both in vitro cell culture and in vivo tissue/tumor system (FIGs. 1-3). Its contribution linearly correlates with cellular redox state, indicated from NADH/NAD+ (FIG. 3C). With an orderly drop of NADH generation from glucose and glutamine, serine catabolism becomes the primary source when cellular respiration is arrested with ETC inhibitors or in hypoxia.
  • T Cell Isolation Kit mouse or Pan T Cell Isolation Kit II, mouse, Miltenyi Biotec Inc.
  • mice were purchased from Jackson Laboratory. The mice were on normal light cycle (7 AM - 7 PM). Invivo infusion was performed on 9-week old normal C57BL/6 mice pre-catheterized on the right jugular vein, and 4-week old NDUFS4 -/- or NDUFS4+/+ mice pre-catheterized on the jugular vein. Infusion was performed for 2.5 h to achieve isotopic pseudo-steady state.
  • mice were fasted from 9:00 am to 2 pm, and infused from 2pm till 4:30 pm. 400mM [2,3,3-2H]serine was dissolved in saline, and infused via the catheter at a constant rate (0.1 pl/min/g mouse weight) using a Just infusion Syringe Pump. At the end of infusion, mice were dissected and tissues were clamped in aluminum foil and stored in liquid nitrogen.
  • NDUFS4 -/- mice were housed with normal mice and gel food was supplied to guarantee sufficient food supply. Mice were grouped as vehicle control group and SHIN2 treatment groups. SHIN2 was dissolved in 20% 2-hydroxypropyl-cyclodextrin solution, and delivered by intraperitoneal (50 pg/g mice) b.i.d. Mice weights were recorded every day. Limb clasps were recorded daily, with mice annotated as having the pathological limb clasping phenotype on the third consecutive day of clasping. 20% weight loss of the peak weight for each mouse is considered as the humane endpoint. [00430] Mouse Xenograft and allograft.
  • Adherent cells Cells were seeded in 6 well plates overnight and then were treated with ETC inhibitors. Serine-free DMEM with 10% dialyzed FBS was supplemented with 400 pM [2,3,3, 2H]serine. Mediumwas replaced by the isotope tracing medium with corresponding drugs, and cells were incubated for 3 h. Medium was aspirated, and metabolism was quenched with extraction buffer (40:40:20 acetonitrile:methanol: water with 0.5% formic acid; 40 pi of extraction solvent per 1 pi packed cell volume)(Lu et ak, 2018). Plates were placed on dry ice for
  • LC-MS LC separation was achieved using a Vanquish UHPLC system (Thermo Fisher Scientific) and an Xbridge BEH Amide column (150x2mm, 2.5 pm particle size; Waters, Milford, MA), column temperature 25°C.
  • Solvent A is 95:5 water: acetonitrile with 20 mM ammonium acetate and 20 mM ammonium hydroxide at pH 9.4, and solvent B is acetonitrile.
  • the gradient was 0 min, 85% B; 2 min, 85% B; 3 min, 60% B; 9 min, 60% B; 9.5 min, 35% B;
  • a second scan from m/z 640-765 with a resolution (at m/z 200) of 35,000 (AGC target 5e5, maximum IT 200ms) was used to measure NAD(P), NAD(P)H, and their labeling.
  • the purpose of the second scan was to enhance sensitivity for NAD(P)(H) by restricting the range of ions in the orbitrap and to maximize the accuracy of isotope ratios by decreasing the scan range and mass resolution (Su et al., 2017).
  • Natural isotope abundance correction Accucor was used to correct all of data except NADH from mice ( Figure IE) for natural isotope abundance (Su et al., 2017). For NADH data from mice, it was necessary to correct also for the interfering peak (non-NADH peak in Figure IF). For this purpose, data were corrected using Elemcor, using unlabeled tissue data as the background (Du et ak, 2019; Millard et ah, 2012). The background correction approach is necessary because orbitrap (Q-Exactive, resolution 78K at 660 m/z) cannot resolve the 2H- NADH peak neatly from either the 13C-NADH peak or the non-NADH interfering peak.
  • FT-ICR MS was used to resolve M+l 2H NADH from M+l 13C NADH (only for Figure IE). Analysis was carried out using a 9.4 T Bruker SolariX FT-ICR MS (Bruker Daltonics Inc., MA, USA) with an ESI source in negative mode. Continuous accumulation of selected ions (CASI) was utilized to increase sensitivity. The CASI window was 50 mass units with a center mass of 660. The ion accumulation time was set to 60 ms.
  • Enzymatic assay for PDH and KGDH Pyruvate dehydrogenase and alpha- ketoglutarate dehydrogenase solutions were freshly prepared to a concentration 0.075unit/ml with buffer containing 20 mM sodium phosphate and 1 mM MgC12, pH7.2. A mixture of thiamine pyrophosphate and Coenzyme A was freshly prepared in the same buffer and diluted by 5 times before use. NAD and NADH solutions were freshly prepared in the buffer through a serial dilution; sodium pyruvate and alpha-ketoglutarate solutions were prepared in buffer in a stock 52 concentration of lOOmM. All solutions were prepared on ice.
  • Reaction mixtures consisted of a final concentration of 0.015 unit/ml of each enzyme, 0.2mM TPP and 0.5mM CoA, and NAD and NADH as indicated in the Figures. Reaction mixtures were incubated for 5 min at room temperature before initiation of the reaction by addition of substrate to a final concentration of 5 mM using multichannel. The reaction took place at 37°C. The plate was mixed for 5 s in the plate reader, and absorbance at 340 nm recorded as above.
  • Cell Proliferation Assays Cells were seeded in seeded in 96 well plates (Corning 3603) for overnight attachment. Medium (with or without drugs) was changed next day, and cell numbers were recorded using Thermofisher CyQUANT kit.
  • Arterial and venous access was obtained to enable fluid infusion (NaCl 4 - 10 mcg/kg/min), blood pressure monitoring, 49 pharmacological control of blood pressure (0.2 - 2.0 mcg/kg/min dobutamine and 0.1 - 5.0 mcg/kg/min phenylephrine, as required), and blood sampling.
  • the primary initiative venous access was via ultrasound-guided percutaneous puncture of the external jugular vein. Arterial access was through the neck to the carotid artery. The surgical site was blocked with Bupivacaine SQ just after the first incision. The subcutaneous tissues and muscle layers were carefully dissected, with hemostasis achieved with electrocautery.
  • a catheter was placed on each vein.
  • Blood from inferior vena cava, internal jugular vein, femoral vein, renal vein, splenic vein, inferior pancreatic vein, inferior mesenteric vein, lateral auricular vein, and coronary sinus were obtained by drawing with a 27G needle connected to 1 mL syringe. Blood was drawn from each vessel twice at 1 - 2 min intervals, except for the coronary sinus (only a single draw). After completion of blood sampling, the animal was euthanized. Blood samples were placed at room temperature for 10 - 20 min, and centrifuged at 1,000 x g for 10 min to obtain serum. Data represents the median value for triplicate technical replicates.
  • mice B6.129S4-Ndufs4+/- mice were purchased from Jackson laboratories. The mice are heterozygous for a protein in mitochondrial complex 1 and have been bred to generate homozygous knockout mouse for the study of mitochondrial deficiency. These mice are a model of mitochondrial disease and knockouts are healthy until approximately 5 weeks age, but develop lethal encephalomyopathy by 7 weeks.
  • [2,3,3- 2 H] serine is an isotope tracer useful for determining whether one-carbon (1C) units for thymidine synthesis are generated via cytosolic or mitochondrial serine catabolism (FIG. 1 A).
  • 1C 1-carbon
  • FIG. IB High-resolution mass spectrometry confirmed that the labeled peak was 2 H-malate (as opposed to natural abundance 13 C-malate) (FIGS. 1C, 8A).
  • Reported values are normalized to circulating [2,3,3- 2 H] serine labeling (i.e. fraction of serum serine labeled but do not include any other correction factors. While the raw extent of malate labeling was small, due to tracer loss via H-D exchange, even modest 2 H labeling is often biologically meaningful.
  • a distinguishing feature of the lC-NADH pathway is transfer of 2 H from serine to malate without carbon transfer. Indeed, in most organs (with exceptions being the liver and brain), 2 H malate labeling from [2,3,3- 2 H] serine in excess of 13 C transfer from [U- 13 C] serine was observed (FIG. 8D).
  • the key redox enzyme of the 1C-NADH pathway is MTHFD2. Labeling of NADH and malate from 2 H-serine was highest in pancreas, which also had the highest MTHFD2 gene expression (FIG. 8E) and greatest serine consumption based on depletion of serine in the draining venous blood (FIG. 8F).
  • Example 2 Serine catabolism is a major NADH source when respiration is impaired.
  • metformin and also phenformin dramatically elevated in the fractional contribution of serine to NADH (FIGs. 2C, 2D, 9C). This enhancement by metformin was seen across a diversity of tumor and normal cell lines (FIG. 2E). Both the basal and metformin-induced serine contribution to NADH occurred via folate-mediated mitochondrial serine catabolism, as it was fully blocked by knockout of the mitochondrial folate enzymes SHMT2 and MTHFD2 (FIG.
  • Intracellular NADH level can well reflect NADH/NAD (FIG. 1 IF).
  • PDH pyruvate dehydrogenase
  • KGDH a- ketoglutarate dehydrogenase
  • MTHFD2 malate dehydrogenase
  • MTHFD2 was at least 10-fold less sensitive, maintaining full activity up to 200 mM NADH, a typical level observed in respiration- impaired cells (FIGs. 4F, 1 IF).
  • the key redox enzyme of serine catabolism is NADH- resistant, and therefore serine catabolism persists even after other NADH production pathways shut off.
  • Example 5 Loss of mitochondrial serine catabolism paradoxically facilitates cell growth in respiration-impaired cells.
  • Serine catabolism is the primary cellular source of 1C units, which are required for nucleotide synthesis and therefore growth. Inhibition of 1C metabolism with anti-folates is clinically employed to treat proliferative conditions, including cancer and autoimmunity. Thus, serine catabolism is classically considered pro-growth. At the same time, however, maintenance of redox homeostasis is critical to cell growth. To examine whether persistent serine catabolism during respiration impairment might induce a pathologically high NADH/NAD ratio and thereby paradoxically impair cell growth, metabolite levels and growth of MTHFD2 knockout cells, in the presence and absence of complex I inhibitors were studied. Such cells tended to have a lower NADH/NAD ratio under basal conditions, which was significantly lower than wild-type cells after complex I inhibition with metformin, phenformin or rotenone (FIG. 5A).
  • Example 7 Serine’s contribution to NADH is enhanced by Leigh Syndrome mutations.
  • Another cause of respiration impairment is genetic deficiencies of the electron transport chain.
  • diseases including Leigh syndrome, a severe neurological disorder that results in cognitive and motor impairment, typically starting during the first year of life.
  • Leigh Syndrome is caused by diversity of nuclear and mitochondrial DNA mutations that result in impaired respiratory chain function.
  • Fibroblasts from Leigh Syndrome patients and controls were compared and an increased NADH/NAD ratio and 2 H- serine contribution to NADH and malate in the patient fibroblasts were observed (FIGs. 7A-7C).
  • MTOl an enzyme involved in mitochondrial tRNA modification and thereby respiratory chain translation.
  • FIG. 14A In genetically engineered colon cancer cells lacking this gene, an increased serine contribution to NADH both in cell culture and as xenograft tumors was observed (FIG. 14A). Moreover, pharmacological blockade of mitochondrial serine metabolism increased these cells’ aspartate level and growth rate (FIGs. 14B-14C).
  • NDUFS4-/- mice have emerged as a useful model for mitochondrial diseases including Leigh Syndrome. Consistent with defective oxidative metabolic capacity and decreased whole-body oxygen uptake, NDUFS4-/- mice manifested lower circulatory turnover flux of glutamine. The fractional contribution of carbohydrate (as measured by TCA labeling from U-13C-glucose) and U- 13 Cglutamine to TCA metabolism was not dramatically altered in the complex I-deficient mice, with the notable exception of a decreased glutamine TCA contribution in pancreas and liver.
  • TCA isotope labeling patterns did not shift much, with no evidence for decreased PDH flux (as measured by M+2/M+3 malate labeling from U- 13 C-glucose) or increased reductive carboxylation (as measured by increased M+3/M+4 malate labeling from U- 13 C-glutamine).
  • Infusion of [2,3,3- 2 H]serine revealed increased 2 H-malate labeling in the mutant mice, which was most evident in the pancreas but also occurred with incomplete penetrance in liver and spleen, the other two major organs to use serine as an NADH supplier (FIGs. IB, 7D).
  • T cells from NDUFS4-/- mice Upon in vitro stimulation, T cells from NDUFS4-/- mice also showed increased NADH/NAD and serine contribution to NADH.
  • mitochondrial genetic mutations enhance serine’s contribution to NADH both in vitro and in vivo.
  • mice Mice heterozygous for the deleted Ndufs4 allele (KO mice) are indistinguishable from wild-type mice.
  • P21 postnatal day 21
  • most Ndufs4 homozygous mice are smaller than normal and begin to lose their body hair; however, their hair generally grows back during the next hair-growth cycle.
  • KO mice reached a maximum body weight of ⁇ 15 g at ⁇ P30.
  • the KO mice Prior to P30, the KO mice are healthy, and they groom themselves, eat normally, responded to novel objects, socialize, and generally behave similar to control mice. They have normal locomotor activity during both day and night until ⁇ P35, after which they gradually became lethargic.
  • Treatment strategy Mice were grouped as vehicle treatment group and KDG112 treatment group. KDG112 was dissolved in 20% hydroxypropyl cyclodextrin to a final concentration of 5mg/ml. Mice were dosed B.I.D at 50 mg/kg ip. Mice weight and body temperature are recorded, and body condition score were given according to the chart below.
  • NADH sources in different physiological and pathological contexts (Chen et ah, 2018; Gaude et ah, 2018; Guarente, 2008; McKenna et ah, 2006; Owen et ah, 2002; Solaini et ah, 2010; Yang et ah, 2014; Yaniv et ah, 2013).
  • a limitation of these studies has been inferring NADH sources based on tracking carbon flows, even though the key energy-carrying functional group in NADH is actually the redox-active hydrogen.
  • NADH sources were directly measured using heavy hydrogen (deuterium), revealing that serine is a substantial NADH source.
  • Serine contributes to NADH independent from the TCA cycle, via folate-mediated mitochondrial serine catabolism.
  • the enzyme SHMT2 converts serine to glycine with concomitant production of methylene-THF.
  • the enzyme MTHFD2 then transfers electrons from methylene-THF to NAD, producing 10-formyl-THF and NADH.
  • MTHFD2 is resistant to product inhibition by NADH, the activity of these enzymes persists when respiration is impaired. Accordingly, when respiration is impaired, even though the absolute flux through serine catabolism likely does not increase, the fraction of NADH made by serine catabolism rises.
  • serine pathway to modulate NADH status. For example, one can envision feeding excess serine and thereby overloading hypoxic tumors with NADH. Conversely, serine catabolism inhibitors might mitigate NADH buildup during ischemic events, reducing suffering in diseases of chronic vascular insufficiency and/or enabling safer reperfusion in acute events.
  • ElemCor accurate data analysis and enrichment calculation for high-resolution LC-MS stable isotope labeling experiments.
  • Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem 275, 223-228.
  • mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome. Science 342 , 1524-1528.
  • Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 510, 542-+.
  • HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption.
  • Cell Metab 3 187-197.
  • Mitochondrial diseases the contribution of organelle stress responses to pathology. Nat Rev Mol Cell Biol 19, 77-92.
  • IACS-10759 is a potent mitochondrial complex I inhibitor with efficacy in inhibiting tumor growth and inducing apoptosis in models of brain cancer and acute myeloid leukemia. Molina, J. R. et ah, Nat. Med. 24, 1036-1046 (2016). Oral gavaging of IACS-10759 (10 mg/kg) to mice xenograft with HCT116 colon cancer cells increased intra-tumor lactate level and NADH/NAD ratio, reflecting its strong inhibition of tumor respiration in vivo. To check whether circulating serine contributes NADH when respiration is impaired in vivo, [2,3,3- 2 H]serine was infused into tumor bearing mice.
  • mice were supplied with high serine drinking water (5%) or metformin drinking water (0.25%) or high serine and metformin drinking water.
  • the metabolomics analysis showed that serine and/or metformin in drinking water can significantly increase NADH/NAD ratio in liver, reflecting the reductive stress caused by serine and metformin.
  • the results of the high serine/metformin drinking water experiment are shown in FIG. 17.

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Abstract

La présente invention concerne, dans divers modes de réalisation, des procédés de traitement de divers troubles et maladies à médiation par NADH chez un sujet, tels que des troubles caractérisés par un excès de NADH, par exemple, par inhibition du catabolisme de la sérine chez le sujet.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11759453B2 (en) 2015-03-10 2023-09-19 The Trustees Of Princeton University SHMT inhibitors
WO2024192049A1 (fr) * 2023-03-15 2024-09-19 Board Of Regents, The University Of Texas System Procédés d'induction de la ferroptose dans le cancer

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4235871A (en) 1978-02-24 1980-11-25 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
US4501728A (en) 1983-01-06 1985-02-26 Technology Unlimited, Inc. Masking of liposomes from RES recognition
US4737323A (en) 1986-02-13 1988-04-12 Liposome Technology, Inc. Liposome extrusion method
US4837028A (en) 1986-12-24 1989-06-06 Liposome Technology, Inc. Liposomes with enhanced circulation time
WO2001062726A2 (fr) 2000-02-23 2001-08-30 Ucb, S.A. Derives de 2-oxo-1-pyrrolidine, procedes de preparation et utilisations desdits derives
WO2015049149A1 (fr) 2013-10-01 2015-04-09 Nobel Biocare Services Ag Kit de pièces dentaires et son procédé d'assemblage
US20180072751A1 (en) 2016-09-14 2018-03-15 The Trustees Of Princeton University SHMT Inhibitors
US20180117010A1 (en) 2015-03-10 2018-05-03 The Trustees Of Princeton University SHMT Inhibitors

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4235871A (en) 1978-02-24 1980-11-25 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
US4501728A (en) 1983-01-06 1985-02-26 Technology Unlimited, Inc. Masking of liposomes from RES recognition
US4737323A (en) 1986-02-13 1988-04-12 Liposome Technology, Inc. Liposome extrusion method
US4837028A (en) 1986-12-24 1989-06-06 Liposome Technology, Inc. Liposomes with enhanced circulation time
WO2001062726A2 (fr) 2000-02-23 2001-08-30 Ucb, S.A. Derives de 2-oxo-1-pyrrolidine, procedes de preparation et utilisations desdits derives
WO2015049149A1 (fr) 2013-10-01 2015-04-09 Nobel Biocare Services Ag Kit de pièces dentaires et son procédé d'assemblage
US20180117010A1 (en) 2015-03-10 2018-05-03 The Trustees Of Princeton University SHMT Inhibitors
US20180072751A1 (en) 2016-09-14 2018-03-15 The Trustees Of Princeton University SHMT Inhibitors
US10077273B2 (en) 2016-09-14 2018-09-18 The Trustees Of Princeton University SHMT inhibitors

Non-Patent Citations (95)

* Cited by examiner, † Cited by third party
Title
"Handbook of Pharmaceutical Additives", 2007, GOWER PUBLISHING CO.
"Pharmaceutical Preformulation and Formulation", 2004, CRC PRESS LLC
"Remington: The Science and Practice of Pharmacy", 2006, THE PHARMACEUTICAL PRESS AND THE AMERICAN PHARMACEUTICAL ASSOCIATION, article "Pharmaceutical Manufacturing", pages: 691 - 1092,958-989
"The Deuterium Isotope Effect", CHEM REV, vol. 55, pages 713 - 743
ASAI, A. ET AL.: "Drug discovery of anticancer drugs targeting methylenetetrahydrofolate dehydrogenase 2", HELIYON 4, vol. 4, 17 December 2018 (2018-12-17), pages e01021
BEN-SAHRA, I., HOXHAJ, G., RICOULT, S.J.H., ASARA, J.M., MANNING, B.D.: "mTORCl induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle", SCIENCE, vol. 351, 2016, pages 728 - 733
BERGE ET AL., JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 66, 1977, pages 1 - 19
BIRSOY, K.WANG, T.CHEN, W.W.FREINKMAN, E.ABU-REMAILEH, M.SABATINI, D.M.: "An Essential Role of the Mitochondrial Electron Transport Chain in Cell Proliferation Is to Enable Aspartate Synthesis", CELL, vol. 162, 2015, pages MEDI-366 - 551
CHABNER, B.A.ROBERTS, T.G., JR.: "Timeline: Chemotherapy and the war on cancer", NATURE REVIEWS CANCER, vol. 5, 2005, pages 65 - 72
CHANDEL, N.S., MALTEPE, E., GOLDWASSER, E., MATHIEU, C.E., SIMON, M.C., SCHUMACKER, P. T.: "Mitochondrial reactive oxygen species trigger hypoxia-induced transcription", PROC NATL ACAD SCI U S A, vol. 95, 1998, pages 11715 - 11720, XP055251050, DOI: 10.1073/pnas.95.20.11715
CHEN, Q.Y.KIRK, K.SHURUBOR, Y.I.ZHAO, D.Z.ARREGUIN, A.J.SHAHI, I.VALSECCHI, F.PRIMIANO, G.CALDER, E.L.CARELLI, V. ET AL.: "Rewiring of Glutamine Metabolism Is a Bioenergetic Adaptation of Human Cells with Mitochondrial DNA Mutations", CELL METABOLISM, vol. 27, 2018, pages 1007
DARIN, N.OLDFORS, A.MOSLEMI, A.R.HOLME, E.TULINIUS, M.: "The incidence of mitochondrial encephalomyopathies in childhood: clinical features and morphological, biochemical, and DNA abnormalities", ANNALS OF NEUROLOGY, vol. 49, 2001, pages 377 - 383
DEBERARDINIS, R.J.LUM, J.J.HATZIVASSILIOU, G.THOMPSON, C.B.: "The biology of cancer: Metabolic reprogramming fuels cell growth and proliferation", CELL METABOLISM, vol. 7, 2008, pages 11 - 20
DEKHNE AAMOD S. ET AL: "Cellular Pharmacodynamics of a Novel Pyrrolo[3,2- d ]pyrimidine Inhibitor Targeting Mitochondrial and Cytosolic One-Carbon Metabolism", MOLECULAR PHARMACOLOGY, vol. 97, no. 1, 9 November 2019 (2019-11-09), US, pages 9 - 22, XP055789718, ISSN: 0026-895X, Retrieved from the Internet <URL:https://molpharm.aspetjournals.org/content/molpharm/97/1/9.full.pdf?with-ds=yes> DOI: 10.1124/mol.119.117937 *
DEKHNE AAMOD S. ET AL: "Novel Pyrrolo[3,2- d ]pyrimidine Compounds Target Mitochondrial and Cytosolic One-carbon Metabolism with Broad-spectrum Antitumor Efficacy", MOLECULAR CANCER THERAPEUTICS, vol. 18, no. 10, 9 July 2019 (2019-07-09), pages 1787 - 1799, XP055789721, ISSN: 1535-7163, Retrieved from the Internet <URL:https://mct.aacrjournals.org/content/molcanther/18/10/1787.full.pdf> DOI: 10.1158/1535-7163.MCT-19-0037 *
DIEHL, F.F.LEWIS, C.A.FISKE, B.P.VANDER HEIDEN, M.G.: "Cellular redox state constrains serine synthesis and nucleotide production to impact cell proliferation", NATURE METABOLISM, vol. 1, 2019, pages 861 - 867
DU, D., TAN, L., WANG, Y., PENG, B., WEINSTEIN, J.N., WONDISFORD, F.E., SU, X., LORENZI, P. L.: "ElemCor: accurate data analysis and enrichment calculation for high-resolution LC-MS stable isotope labeling experiments", BMC BIOINFORMATICS, vol. 20, 2019, pages 89
DUCKER, G.S.CHEN, L.MORSCHER, R.J.GHERGUROVICH, J.M.ESPOSITO, M.TENG, X.KANG, Y.RABINOWITZ, J.D.: "Reversal of Cytosolic One-Carbon Flux Compensates for Loss of the Mitochondrial Folate Pathway", CELL METABOLISM, vol. 24, 2016, pages 640 - 641
DUCKER, G.S.GHERGUROVICH, J.M.MAINOLFI, N.SURI, V.JEONG, S.K.HSIN-JUNG LI, S.FRIEDMAN, A.MANFREDI, M.G.GITAI, Z.KIM, H. ET AL.: "Human SHMT inhibitors reveal defective glycine import as a targetable metabolic vulnerability of diffuse large B-cell lymphoma", PROC NATL ACAD SCI U S A, vol. 114, 2017, pages 11404 - 11409
EADSFORTH, T.C. ET AL.: "Acinetobacter baumannii FolD ligand complexes --potent inhibitors of folate metabolism and a re-evaluation of the structure ofLY374571", FEBS J, vol. 279, no. 23, December 2012 (2012-12-01), pages 4350 - 60
EADSFORTH, T.C. ET AL.: "Characterization of 2,4-Diamino-6-oxo-1, 6-dihydropyrimidin-5-yl Ureido Based Inhibitors of Trypanosoma brucei FolD and Testing for Antiparasitic Activity", J MED CHEM., vol. 58, no. 20, 22 October 2015 (2015-10-22), pages 7938 - 48, XP055590890, DOI: 10.1021/acs.jmedchem.5b00687
EL-MIR, M.Y.NOGUEIRA, V.FONTAINE, E.AVERET, N.RIGOULET, M.LEVERVE, X.: "Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I", J BIOL CHEM, vol. 275, 2000, pages 223 - 228
FAKRUDDIN, M.WEI, F.Y.SUZUKI, T.ASANO, K.KAIEDA, T.OMORI, A.IZUMI, R.FUJIMURA, A.KAITSUKA, T.MIYATA, K. ET AL.: "Defective Mitochondrial tRNA Taurine Modification Activates Global Proteostress and Leads to Mitochondrial Disease", CELL REP, vol. 22, 2018, pages 482 - 496
FERRARI, M.JAIN, I.H.GOLDBERGER, O.REZOAGLI, E.THOONEN, R.CHEN, K.H.SOSNOVIK, D.E.SCHERRER- CROSBIE, M.MOOTHA, V.K.ZAPOL, W.M.: "Hypoxia treatment reverses neurodegenerative disease in a mouse model of Leigh syndrome", P NATL ACAD SCI USA, vol. 114, 2017, pages E4241 - E4250
FU. C. ET AL.: "The natural product carolacton inhibits folate dependent CI metabolism by targeting FolD/ MTHFD", NATURE COMM, vol. 8, 2017
FUJII, T.NOZAKI, F.SAITO, K.HAYASHI, A.NISHIGAKI, Y.MURAYAMA, K.TANAKA, M.KOGA, Y.HIEJIMA, I.KUMADA, T.: "Efficacy of pyruvate therapy in patients with mitochondrial disease: A semiquantitative clinical evaluation study", MOL GENET METAB, vol. 112, 2014, pages 133 - 138
FULLER, N.O. ET AL.: "An improved model for fragment-based lead generation at AstraZeneca", DRUG DISCOV TODAY, vol. 21, no. 8, 2016, pages 1272 - 83, XP029680971, DOI: 10.1016/j.drudis.2016.04.023
FULLERTON, M.D.GALIC, S.MARCINKO, K.SIKKEMA, S.PULINILKUNNIL, T.CHEN, Z.P.O'NEILL, H.M.FORD, R.J.PALANIVEL, R.O'BRIEN, M. ET AL.: "Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin", NAT MED, vol. 19, 2013, pages 1649 - 1654
GAMEIRO, P.A.YANG, J.J.METELO, A.M.PEREZ-CARRO, R.BAKER, R.WANG, Z.W.ARREOLA, A.RATHMELL, W.K.OLUMI, A.LOPEZ-LARRUBIA, P. ET AL.: "Vivo HIF-Mediated Reductive Carboxylation Is Regulated by Citrate Levels and Sensitizes VHL-Deficient Cells to Glutamine Deprivation", CELL METAB, vol. 17, 2013, pages 372 - 385
GAUDE, E.SCHMIDT, C.GAMMAGE, P.A.DUGOURD, A.BLACKER, T.CHEW, S.P.SAEZ-RODRIGUEZ, J.O'NEILL, J.S.SZABADKAI, G.MINCZUK, M. ET AL.: "NADH Shuttling Couples Cytosolic Reductive Carboxylation of Glutamine with Glycolysis in Cells with Mitochondrial Dysfunction", MOL CELL, vol. 69, 2018, pages 581 - 593
GEERAERTS SHAUNI LIEN ET AL: "Repurposing the Antidepressant Sertraline as SHMT Inhibitor to Suppress Serine/Glycine Synthesis-Addicted Breast Tumor Growth", MOLECULAR CANCER THERAPEUTICS, vol. 20, no. 1, 17 November 2020 (2020-11-17), pages 50 - 63, XP055789200, ISSN: 1535-7163, Retrieved from the Internet <URL:https://mct.aacrjournals.org/content/molcanther/early/2020/12/10/1535-7163.MCT-20-0480.full.pdf> DOI: 10.1158/1535-7163.MCT-20-0480 *
GRAVEL SIMON-PIERRE ET AL: "Serine Deprivation Enhances Antineoplastic Activity of Biguanides", CANCER RESEARCH, vol. 74, no. 24, 6 November 2014 (2014-11-06), pages 7521 - 7533, XP055789137, ISSN: 0008-5472, Retrieved from the Internet <URL:https://cancerres.aacrjournals.org/content/canres/74/24/7521.full.pdf> DOI: 10.1158/0008-5472.CAN-14-2643-T *
GREGORY, J.F.CUSKELLY, G.J.SHANE, B.TOTH, J.P.BAUMGARTNER, T.G.STACPOOLE, P.W.: "Primed, constant infusion with [2H3]serine allows in vivo kinetic measurement of serine turnover, homocysteine remethylation, and transsulfuration processes in human one-carbon metabolism", AM J CLIN NUTR, vol. 72, 2000, pages 1535 - 1541
GUARENTE, L.: "Mitochondria--a nexus for aging, calorie restriction, and sirtuins?", CELL, vol. 132, 2008, pages 171 - 176
HENG, J.S.RATTNER, A.STEIN-O'BRIEN, G.L.WINER, B.L.JONES, B.W.VERNON, H.J.GOFF, L.A.NATHANS, J.: "Hypoxia tolerance in the Norrin-deficient retina and the chronically hypoxic brain studied at single-cell resolution", P NATL ACAD SCI USA, vol. 116, 2019, pages 9103 - 9114
HERBIG, K.CHIANG, E.P.LEE, L.R.HILLS, J.SHANE, B.STOVER, P.J.: "Cytoplasmic serine hydroxymethyltransferase mediates competition between folate-dependent deoxyribonucleotide and Sadenosylmethionine biosyntheses", J BIOL CHEM, vol. 277, 2002, pages 38381 - 38389
HUI, S.GHERGUROVICH, J.M.MORSCHER, R.J.JANG, C.TENG, X.LU, W.ESPARZA, L.A.REYA, T.LE, Z.YANXIANG GUO, J. ET AL.: "Glucose feeds the TCA cycle via circulating lactate", NATURE, vol. 551, 2017, pages 115 - 118
HUNTER, R.W.HUGHEY, C.C.LANTIER, L.SUNDELIN, E.I.PEGGIE, M.ZEQIRAJ, E.SICHERI, F.JESSEN, N.WASSERMAN, D.H.SAKAMOTO, K.: "Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase", NAT MED, vol. 24, 2018, pages 1395, XP036902354, DOI: 10.1038/s41591-018-0159-7
JAIN, I.H.ZAZZERON, L.GOLDBERGER, O.MARUTANI, E.WOJTKIEWICZ, G.R.AST, T.WANG, H.SCHLEIFER, G.STEPANOVA, A.BREPOELS, K. ET AL.: "Leigh Syndrome Mouse Model Can Be Rescued by Interventions that Normalize Brain Hyperoxia, but Not HIF Activation", CELL METAB, vol. 30, 2019, pages 824, XP085846897, DOI: 10.1016/j.cmet.2019.07.006
JAIN, I.H.ZAZZERON, L.GOLI, R.ALEXA, K.SCHATZMAN-BONE, S.DHILLON, H.GOLDBERGER, O.PENG, J.SHALEM, O.SANJANA, N.E. ET AL.: "Hypoxia as a therapy for mitochondrial disease", SCIENCE, vol. 352, 2016, pages 54 - 61, XP055696083, DOI: 10.1126/science.aad9642
JOHNSON, S.C.YANOS, M.E.KAYSER, E.B.QUINTANA, A.SANGESLAND, M.CASTANZA, A.UHDE, L.HUI, J.WALL, V.Z.GAGNIDZE, A. ET AL.: "mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome", SCIENCE, vol. 342, 2013, pages 1524 - 1528, XP009520188, DOI: 10.1126/science.1244360
KALUCKA, J.BIERHANSL, L.CONCHINHA, N.V.MISSIAEN, R.ELIA, I.BRUNING, U.SCHEINOK, S.TREPS, L.CANTELMO, A.R.DUBOIS, C. ET AL.: "Quiescent Endothelial Cells Upregulate Fatty Acid (beta-Oxidation for Vasculoprotection via Redox Homeostasis", CELL METABOLISM, vol. 28, 2018, pages 881
KERR, D.S.: "Review of clinical trials for mitochondrial disorders", NEUROTHERAPEUTICS, vol. 10, 1997, pages 307 - 319, XP035352264, DOI: 10.1007/s13311-013-0176-7
KHAN, N.A.NIKKANEN, J.YATSUGA, S.JACKSON, C.WANG, L.Y.PRADHAN, S.KIVELA, R.PESSIA, A.VELAGAPUDI, V.SUOMALAINEN, A.: "mTORCl Regulates Mitochondrial Integrated Stress Response and Mitochondrial Myopathy Progression", CELL METABOLISM, vol. 26, 2017, pages 419, XP085151034, DOI: 10.1016/j.cmet.2017.07.007
KREMER, J.M.: "The mechanism of action of methotrexate in rheumatoid arthritis: the search continues", THE JOURNAL OF RHEUMATOLOGY, vol. 21, 1994, pages 1 - 5
LIU, L.SHAH, S.FAN, J.PARK, J.O.WELLEN, K.E.RABINOWITZ, J.D.: "Malic enzyme tracers reveal hypoxia-induced switch in adipocyte NADPH pathway usage", NATURE CHEMICAL BIOLOGY, vol. 12, 2016, pages 345 - 352
LIU, X.J.ROMERO, I.L.LITCHFIELD, L.M.LENGYEL, E.LOCASALE, J.W.: "Metformin Targets Central Carbon Metabolism and Reveals Mitochondrial Requirements in Human Cancers", CELL METABOLISM, vol. 24, 2016, pages 728 - 739, XP029804635, DOI: 10.1016/j.cmet.2016.09.005
LU, W.Y.WANG, L.CHEN, L.HUI, S.RABINOWITZ, J.D., EXTRACTION AND QUANTITATION OF NICOTINAMIDE ADENINE DINUCLEOTIDE REDOX COFACTORS. ANTIOXID REDOX SIGN, vol. 28, 2018, pages 167 - 179
LUNDSGAARD, A.M.FRITZEN, A.M.KIENS, B.: "Molecular Regulation of Fatty Acid Oxidation in Skeletal Muscle during Aerobic Exercise", TRENDS ENDOCRIN MET, vol. 29, 2018, pages 18 - 30, XP085311512, DOI: 10.1016/j.tem.2017.10.011
LUNT, S.Y.VANDER HEIDEN, M.G.: "Aerobic Glycolysis: Meeting the Metabolic Requirements of Cell Proliferation", ANNU REV CELL DEV BI, vol. 27, 2011, pages 441 - 464
MADIRAJU, A.K.ERION, D.M.RAHIMI, Y.ZHANG, X.M.BRADDOCK, D.T.ALBRIGHT, R.A.PRIGARO, B.J.WOOD, J.L.BHANOT, S.MACDONALD, M.J. ET AL.: "Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase", NATURE, vol. 510, 2014, pages 542
MADIRAJU, A.K.QIU, Y.PERRY, R.J.RAHIMI, Y.ZHANG, X.M.ZHANG, D.Y.CAMPOREZ, J.P.G.CLINE, G.W.BUTRICO, G.M.KEMP, B.E. ET AL.: "Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo", NAT MED, vol. 24, 2018, pages 1384, XP036902341, DOI: 10.1038/s41591-018-0125-4
MARTINEZ-REYES, I.CHANDEL, N.S.: "Mitochondrial One-Carbon Metabolism Maintains Redox Balance during Hypoxia", CANCER DISCOVERY, vol. 4, 2014, pages 1371 - 1373
MCKENNA, M.C.WAAGEPETERSEN, H.S.SCHOUSBOE, A.SONNEWALD, U.: "Neuronal and astrocytic shuttle mechanisms for cytosolic-mitochondrial transfer of reducing equivalents: Current evidence and pharmacological tools", BIOCHEM PHARMACOL, vol. 71, 2006, pages 399 - 407, XP025043094, DOI: 10.1016/j.bcp.2005.10.011
MEISER JOHANNES ET AL: "Serine one-carbon catabolism with formate overflow", SCIENCE ADVANCES, vol. 2, no. 10, 1 October 2016 (2016-10-01), pages e1601273, XP055789146, Retrieved from the Internet <URL:https://advances.sciencemag.org/content/2/10/e1601273.full.pdf> DOI: 10.1126/sciadv.1601273 *
MILLARD, P.LETISSE, F.SOKOL, S.PORTAIS, J.C.: "IsoCor: correcting MS data in isotope labeling experiments", BIOINFORMATICS, vol. 28, 2012, pages 1294 - 1296
MOLINA, J. R. ET AL.: "IACS-10759 is a potent mitochondrial complex I inhibitor with efficacy in inhibiting tumor growth and inducing apoptosis in models of brain cancer and acute myeloid leukemia", NAT. MED., vol. 24, 2018, pages 1036 - 1046
MULLARKY, E. ET AL.: "A novel small-molecule inhibitor of 3-phosphoglycerate dehydrogenase", MOL CELL ONCOL, vol. 3, no. 4, 2016, pages e 1164280
MULLARKY, E. ET AL.: "Identification of a small molecule inhibitor of 3-phosphoglycerate dehydrogenase to target serine biosynthesis in cancers", PROC NATL ACAD SCI U S A, vol. 113, no. 7, 2016, pages 1778 - 83, XP055352948, DOI: 10.1073/pnas.1521548113
MULLEN, A.R.WHEATON, W.W.JIN, E.S.CHEN, P.H.SULLIVAN, L.B.CHENG, T.YANG, Y.F.LINEHAN, W.M.CHANDEL, N.S.DEBERARDINIS, R.J.: "Reductive carboxylation supports growth in tumour cells with defective mitochondria", NATURE, vol. 481, 2012, pages 385 - U171
MURAYAMA, K.SHIMURA, M.LIU, Z.OKAZAKI, Y.OHTAKE, A.: "Recent topics: the diagnosis, molecular genesis, and treatment of mitochondrial diseases", J HUM GENET, vol. 64, 2019, pages 113 - 125, XP036668947, DOI: 10.1038/s10038-018-0528-6
NEINAST, M.D.JANG, C.HUI, S.MURASHIGE, D.S.CHU, Q.MORSCHER, R.J.LI, X.ZHAN, L.WHITE, E.ANTHONY, T.G. ET AL.: "Quantitative Analysis of the Whole-Body Metabolic Fate of Branched-Chain Amino Acids", CELL METABOLISM, vol. 29, 2019, pages 417 - 429
NIKKANEN, J.FORSSTROM, S.EURO, L.PAETAU, I.KOHNZ, R.A.WANG, L.Y.CHILOV, D.VIINAMAKI, J.ROIVAINEN, A.MAIJAMAKI, P. ET AL.: "Mitochondrial DNA Replication Defects Disturb Cellular dNTP Pools and Remodel One-Carbon Metabolism", CELL METAB, vol. 23, 2016, pages 635 - 648, XP029504667, DOI: 10.1016/j.cmet.2016.01.019
OWEN, M.R.DORAN, E.HALESTRAP, A.P.: "Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain", BIOCHEM J, vol. 348, 2000, pages 607 - 614, XP001030855, DOI: 10.1042/0264-6021:3480607
OWEN, O.E.KALHAN, S.C.HANSON, R.W.: "The key role of anaplerosis and cataplerosis for citric acid cycle function", J BIOL CHEM, vol. 277, 2002, pages 30409 - 30412
PACOLD, M. E. ET AL.: "A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate", NAT CHEM BIOL, vol. 12, no. 6, 2016, pages 452 - 8, XP055366719, DOI: 10.1038/nchembio.2070
PACOLD, M.E. ET AL.: "A PHGDH inhibitor reveals coordination of serine synthesis and 1-carbon unit fate", NAT CHEM BIOL., vol. 12, no. 6, June 2016 (2016-06-01), pages 452 - 458, XP055366719, DOI: 10.1038/nchembio.2070
PAPANDREOU, I.CAIRNS, R.A.FONTANA, L.LIM, A.L.DENKO, N.C.: "HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption", CELL METAB, vol. 3, 2006, pages 187 - 197, XP055110894, DOI: 10.1016/j.cmet.2006.01.012
PFEFFER, G.MAJAMAA, K.TURNBULL, D.M.THORBURN, D.CHINNERY, P.F.: "Treatment for mitochondrial disorders", COCHRANE DATABASE SYST REV, 2012, pages CD004426
RAVEZ, S. ET AL.: "alpha-Ketothioamide Derivatives: A Promising Tool to Interrogate. Phosphoglycerate Dehydrogenase (PHGDH)", J MED CHEM, vol. 60, no. 4, 2017, pages 1591 - 1597
RAVEZ, S. ET AL.: "Challenges and Opportunities in the Development of Serine Synthetic Pathway Inhibitors for Cancer Therapy", J MED CHEM, vol. 60, no. 4, 2017, pages 1227 - 1237
RHODE, J.M. ET AL.: "Discovery and optimization of piperazine-I- thiourea-based human phosphoglycerate dehydrogenase inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY
SAITO, K.KIMURA, N.ODA, N.SHIMOMURA, H.KUMADA, T.MIYAJIMA, T.MURAYAMA, K.TANAKA, M.FUJII, T.: "Pyruvate therapy for mitochondrial DNA depletion syndrome", BBA-GEN SUBJECTS, vol. 1820, 2012, pages 632 - 636, XP055228134, DOI: 10.1016/j.bbagen.2011.08.006
SAMANTA, D.PARK, Y.ANDRABI, S.A.SHELTON, L.M.GILKES, D.M.SEMENZA, G.L.: "PHGDH Expression Is Required for Mitochondrial Redox Homeostasis, Breast Cancer Stem Cell Maintenance, and Lung Metastasis", CANCER RES, vol. 76, 2016, pages 4430 - 4442
SCHMIDT, A.WU, H.P.MACKENZIE, R.E.CHEN, V.J.BEWLY, J.R.RAY, J.E.TOTH, J.E.CYGLER, M.: "Structures of three inhibitor complexes provide insight into the reaction mechanism of the human methylenetetrahydrofolate dehydrogenase/cyclohydrolase", BIOCHEMISTRY-US, vol. 39, 2000, pages 6325 - 6335, XP055488386, DOI: 10.1021/bi992734y
SOLAINI, G.BARACCA, A.LENAZ, G.SGARBI, G.: "Hypoxia and mitochondrial oxidative metabolism", BIOCHIMICA ET BIOPHYSICA ACTA, vol. 1797, 2010, pages 1171 - 1177
SU, X.LU, W.RABINOWITZ, J.D.: "Metabolite Spectral Accuracy on Orbitraps", ANALYTICAL CHEMISTRY, vol. 89, 2017, pages 5940 - 5948
SULLIVAN, L.B.GUI, D.Y.HOSIOS, A.M.BUSH, L.N.FREINKMAN, E.VANDER HEIDEN, M.G.: "Supporting Aspartate Biosynthesis Is an Essential Function of Respiration in Proliferating Cells", CELL, vol. 162, 2015, pages 552 - 563, XP029248054, DOI: 10.1016/j.cell.2015.07.017
SULLIVAN, L.B.LUENGO, A.DANAI, L.V.BUSH, L.N.DIEHL, F.F.HOSIOS, A.M.LAU, A.N.ELMILIGY, S.MALSTROM, S.LEWIS, C.A. ET AL.: "Aspartate is an endogenous metabolic limitation for tumour growth", NAT CELL BIOL, vol. 20, 2018, pages 782, XP036536676, DOI: 10.1038/s41556-018-0125-0
SUOMALAINEN, A.BATTERSBY, B.J.: "Mitochondrial diseases: the contribution of organelle stress responses to pathology", NAT REV MOL CELL BIOL, vol. 19, 2018, pages 77 - 92, XP055492794, DOI: 10.1038/nrm.2017.66
TITOV, D.V.CRACAN, V.GOODMAN, R.P.PENG, J.GRABAREK, Z.MOOTHA, V.K.: "Complementation of mitochondrial electron transport chain by manipulation of the NAD(+)/NADH ratio", SCIENCE, vol. 352, 2016, pages 231 - 235
TYYNISMAA, H.CARROLL, C.J.RAIMUNDO, N.AHOLA-ERKKILA, S.WENZ, T.RUHANEN, H.GUSE, K.HEMMINKI, A.PELTOLA-MJOSUND, K.E.TULKKI, V. ET A: "Mitochondrial myopathy induces a starvation-like response", HUM MOL GENET, vol. 19, 2010, pages 3948 - 3958
WANG, L.XING, X.CHEN, L.YANG, L.SU, X.RABITZ, H.LU, W.RABINOWITZ, J.D.: "Peak Annotation and Verification Engine for Untargeted LC-MS Metabolomics", ANALYTICAL CHEMISTRY, vol. 91, 2019, pages 1838 - 1846
WANG, Q. ET AL.: "Rational Design of Selective Allosteric Inhibitors of PHGDH and Serine Synthesis with Anti-tumor Activity", CELL CHEM BIOL, vol. 24, no. 1, 2017, pages 55 - 65, XP029890373, DOI: 10.1016/j.chembiol.2016.11.013
WANG. Y. ET AL.: "Deguelin, a novel anti-tumorigenic agent targeting apoptosis, cell cycle arrest and anti-angiogenesis for cancer chemoprevention", MOL CLIN ONCOL, vol. 1, no. 2, March 2013 (2013-03-01), pages 215 - 219
WEINBLATT, M.E.COBLYN, J.S.FOX, D.A.FRASER, P.A.HOLDSWORTH, D.E.GLASS, D.N.TRENTHAM, D.E.: "Efficacy of low-dose methotrexate in rheumatoid arthritis", THE NEW ENGLAND JOURNAL OF MEDICINE, vol. 312, 1985, pages 818 - 822
WHEATON, W.W.WEINBERG, S.E.HAMANAKA, R.B.SOBERANES, S.SULLIVAN, L.B.ANSO, E.GLASAUER, A.DUFOUR, E.MUTLU, G.M.BUDIGNER, G.R.S. ET A: "Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis", ELIFE, vol. 3, 1955
WISE, D.R.WARD, P.S.SHAY, J.E.S.CROSS, J.R.GRUBER, J.J.SACHDEVA, U.M.PLATT, J.M.DEMATTEO, R.G.SIMON, M.C.THOMPSON, C.B.: "Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of alpha-ketoglutarate to citrate to support cell growth and viability", P NATL ACAD SCI USA, vol. 108, 2011, pages 19611 - 19616, XP002736942, DOI: 10.1073/pnas.1117773108
YANG ET AL., CELL METAB, vol. 31, 2020, pages 809 - 821
YANG LIFENG ET AL: "Serine Catabolism Feeds NADH when Respiration Is Impaired", CELL METABOLISM, CELL PRESS, UNITED STATES, vol. 31, no. 4, 17 March 2020 (2020-03-17), pages 809, XP086124077, ISSN: 1550-4131, [retrieved on 20200317], DOI: 10.1016/J.CMET.2020.02.017 *
YANG, C.D.KO, B.HENSLEY, C.T.JIANG, L.WASTI, A.T.KIM, J.SUDDERTH, J.CALVARUSO, M.A.LUMATA, L.MITSCHE, M. ET AL.: "Glutamine Oxidation Maintains the TCA Cycle and Cell Survival during Impaired Mitochondrial Pyruvate Transport", MOL CELL, vol. 56, 2014, pages 414 - 424, XP029095115, DOI: 10.1016/j.molcel.2014.09.025
YANIV, Y.JUHASZOVA, M.SOLLOTT, S.J.: "Age-related changes of myocardial ATP supply and demand mechanisms", TRENDS ENDOCRINOL METAB, vol. 24, 2013, pages 495 - 505
YE, J.FAN, J.VENNETI, S.WAN, Y.W.PAWEL, B.R.ZHANG, J.FINLEY, L.W.LU, C.LINDSTEN, T.CROSS, J.R. ET AL.: "Serine catabolism regulates mitochondrial redox control during hypoxia", CANCER DISCOVERY, vol. 4, 2014, pages 1406 - 1417
YOO, H.ANTONIEWICZ, M.R.STEPHANOPOULOS, G.KELLEHER, J.K.: "Quantifying reductive carboxylation flux of glutamine to lipid in a brown adipocyte cell line", J BIOL CHEM, vol. 283, 2008, pages 20621 - 20627, XP055009342, DOI: 10.1074/jbc.M706494200
ZHANG, Z.CHEN, L.LIU, L.SU, X.RABINOWITZ, J.D.: "Chemical Basis for Deuterium Labeling of Fat and NADPH", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 139, 2017, pages 14368 - 14371

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